U.S. patent application number 14/343983 was filed with the patent office on 2014-08-14 for disubstituted 5-fluoro-pyrimidines.
This patent application is currently assigned to BAYER INTELLECTUAL PROPERTY GMBH. The applicant listed for this patent is Rolf Bohlmann, Ulf Bomer, Dirk Kosemund, Philip Lienau, Ulrich Lucking, Arne Scholz, Gerhard Siemeister. Invention is credited to Rolf Bohlmann, Ulf Bomer, Dirk Kosemund, Philip Lienau, Ulrich Lucking, Arne Scholz, Gerhard Siemeister.
Application Number | 20140228387 14/343983 |
Document ID | / |
Family ID | 46880699 |
Filed Date | 2014-08-14 |
United States Patent
Application |
20140228387 |
Kind Code |
A1 |
Lucking; Ulrich ; et
al. |
August 14, 2014 |
DISUBSTITUTED 5-FLUORO-PYRIMIDINES
Abstract
The present invention relates to disubstituted
5-fluoro-pyrimidines of general formula (I) as described and
defined herein, and methods for their preparation, their use for
the treatment and/or prophylaxis of disorders, in particular of
hyper-proliferative disorders and/or virally induced infectious
diseases and/or of cardiovascular diseases. The invention further
relates to intermediate compounds useful in the preparation of said
compounds of general formula (I).
Inventors: |
Lucking; Ulrich; (Berlin,
DE) ; Kosemund; Dirk; (Berlin, DE) ; Scholz;
Arne; (Berlin, DE) ; Lienau; Philip; (Berlin,
DE) ; Siemeister; Gerhard; (Berlin, DE) ;
Bomer; Ulf; (Glienicke, DE) ; Bohlmann; Rolf;
(Berlin, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lucking; Ulrich
Kosemund; Dirk
Scholz; Arne
Lienau; Philip
Siemeister; Gerhard
Bomer; Ulf
Bohlmann; Rolf |
Berlin
Berlin
Berlin
Berlin
Berlin
Glienicke
Berlin |
|
DE
DE
DE
DE
DE
DE
DE |
|
|
Assignee: |
BAYER INTELLECTUAL PROPERTY
GMBH
Monheim
DE
|
Family ID: |
46880699 |
Appl. No.: |
14/343983 |
Filed: |
September 13, 2012 |
PCT Filed: |
September 13, 2012 |
PCT NO: |
PCT/EP2012/067966 |
371 Date: |
March 10, 2014 |
Current U.S.
Class: |
514/275 ;
544/331; 544/332 |
Current CPC
Class: |
A61P 15/00 20180101;
A61P 13/08 20180101; C07D 239/42 20130101; A61P 11/00 20180101;
A61P 35/00 20180101; A61P 9/00 20180101; C07D 401/12 20130101; C07D
405/04 20130101; A61K 31/505 20130101; A61P 17/00 20180101; C07D
407/04 20130101; A61P 31/12 20180101; A61P 1/04 20180101; A61K
31/506 20130101 |
Class at
Publication: |
514/275 ;
544/332; 544/331 |
International
Class: |
C07D 239/42 20060101
C07D239/42; C07D 401/12 20060101 C07D401/12; A61K 31/506 20060101
A61K031/506; A61K 31/505 20060101 A61K031/505; C07D 405/04 20060101
C07D405/04 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 16, 2011 |
EP |
11181545.2 |
Claims
1. A compound of general formula (I) ##STR00086## wherein R.sup.1
represents a group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.7-cycloalkyl heterocyclyl-, phenyl, heteroraryl,
phenyl-C.sub.1-C.sub.3-alkyl- or heteroaryl-C.sub.1-C.sub.3-alkyl-,
wherein said group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group of hydroxy, cyano, halogen, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines; R.sup.2 represents a group selected from
##STR00087## R.sup.3, R.sup.4 represent, independently from each
other, a group selected from a hydrogen atom, fluoro atom, chloro
atom, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; R.sup.5
represents a group selected from a) a C.sub.1-C.sub.6-alkyl group,
which is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,
wherein said C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl or
heteroaryl group is optionally substituted with one, two or three
substituents, identically or differently, selected from halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; b) a
C.sub.3-C.sub.7-cycloalkyl- group, which is optionally substituted
with one or two or three substituents, identically or differently,
selected from the group of halogen, hydroxy, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-, C.sub.2-C.sub.3-alkenyl-,
C.sub.2-C.sub.3-alkynyl-; c) a heterocyclyl- group, which is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-; d) a phenyl
group, which is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of halogen, hydroxy, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; e) a
heteroaryl group, which is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of halogen, hydroxy, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; f) a
phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; g) a
heteroaryl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; h) a
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl- group, which
C.sub.3-C.sub.6-cycloalkyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; i) a
heterocyclyl-C.sub.1-C.sub.3-alkyl- group, which heterocyclyl group
is optionally substituted with one or two or three substituents,
identically or differently, selected from halogen,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; j)
phenyl-cyclopropyl- group, which phenyl group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, hydroxy, NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-; k) a heteroaryl-cyclopropyl- group, which
heteroaryl group is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of halogen, hydroxy, NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; R.sup.6,
R.sup.7 represent, independently from each other, a group selected
from a hydrogen atom, fluoro atom, chloro atom,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; or its
salts, solvates or salts of solvates.
2. The compound according to claim 1, wherein R.sup.1 represents a
group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally
substituted with one or two substituents, identically or
differently, selected from the group of hydroxy,
C.sub.1-C.sub.2-alkoxy-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-; R.sup.2 represents a group selected
from ##STR00088## R.sup.3 represents a hydrogen atom or a fluoro
atom; R.sup.4 represents a hydrogen atom or a fluoro atom; R.sup.5
represents a group selected from a) a C.sub.1-C.sub.6-alkyl group,
which is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-, C.sub.3-C.sub.7-cycloalkyl-,
heterocyclyl-, phenyl, heteroaryl, wherein said
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl or heteroaryl
group is optionally substituted with one, two or three
substituents, identically or differently, selected from halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-;
b) a phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-; c) a heteroaryl-C.sub.1-C.sub.3-alkyl-
group, which heteroaryl group is optionally substituted with one or
two or three substituents, identically or differently, selected
from the group of halogen, hydroxy, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; d) a
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl- group, which
C.sub.3-C.sub.6-cycloalkyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; e) a
heterocyclyl-C.sub.1-C.sub.3-alkyl- group, which heterocyclyl group
is optionally substituted with one or two or three substituents,
identically or differently, selected from halogen,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; f)
phenyl-cyclopropyl- group, which phenyl group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, hydroxy,
--NH.sub.2, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-; g) a heteroaryl-cyclopropyl- group, which
heteroaryl group is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of halogen, hydroxy, --NH.sub.2, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; R.sup.6,
R.sup.7 represent, independently from each other, a group selected
from a hydrogen atom, fluoro atom, chloro atom,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; or its
salts, solvates or salts of solvates.
3. The compound according to claim 1, wherein R.sup.1 represents a
group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally
substituted with one or two substituents, identically or
differently, selected from the group of hydroxy,
C.sub.1-C.sub.6-alkoxy-; R.sup.2 represents a group selected from
##STR00089## R.sup.3 represents a hydrogen atom or fluoro atom;
R.sup.4 represents a hydrogen atom or a fluoro atom; R.sup.5
represents a group selected from a) a C.sub.1-C.sub.3-alkyl group,
which is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
cyano, halo-C.sub.1-C.sub.3-alkyl-; b) a
phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; c) a
heteroaryl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two substituents, identically or
differently, selected from the group of halogen, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; d) a
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl- group, which
C.sub.3-C.sub.6-cycloalkyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; e) a
heterocyclyl-C.sub.1-C.sub.3-alkyl- group, which heterocyclyl group
is optionally substituted with one or two or three substituents,
identically or differently, selected from halogen,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; f)
phenyl-cyclopropyl- group, which phenyl group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; g) a
heteroaryl-cyclopropyl- group, which heteroaryl group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; R.sup.6,
R.sup.7 represent, independently from each other, a group selected
from a hydrogen atom or a fluoro atom; or its salts, solvates or
salts of solvates.
4. The compound according to claim 1, wherein R.sup.1 represents a
group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally
substituted with one or two substituents, identically or
differently, selected from the group of hydroxy,
C.sub.1-C.sub.6-alkoxy-; R.sup.2 represents a group selected from
##STR00090## R.sup.3 represents a hydrogen atom or fluoro atom;
R.sup.4 represents a hydrogen atom; R.sup.5 represents a group
selected from a) a C.sub.1-C.sub.3-alkyl group; b) a
phenyl-C.sub.1-C.sub.3-alkyl- group; R.sup.6, R.sup.7 represent,
independently from each other, a group selected from a hydrogen
atom or fluoro atom; or its salts, solvates or salts of
solvates.
5. The compound according to claim 1, wherein R.sup.1 represents a
group selected from methyl, ethyl, propan-2yl-, cyclopropyl,
tert-butyl-, cyclohexyl, wherein said group is optionally
substituted with one substituent selected from the group of
hydroxy, methoxy-, C.sub.1-C.sub.6-alkoxy-; R.sup.2 represents a
group selected from 4-fluoro-2-methoxyphenyl-,
2-(benzyloxy)-4-fluorophenyl-, 3,4-dihydro-2H-chromen-8-yl-;
R.sup.3 represents a hydrogen atom or fluoro atom; R.sup.4
represents a hydrogen atom; or its salts, solvates or salts of
solvates.
6. The compound according to claim 1, wherein R.sup.1 represents a
methyl group; R.sup.2 represents a group selected from
4-fluoro-2-methoxyphenyl-, 2-(benzyloxy)-4-fluorophenyl-,
3,4-dihydro-2H-chromen-8-yl-; R.sup.3 represents a hydrogen atom or
fluoro atom; R.sup.4 represents a hydrogen atom; or its salts,
solvates or salts of solvates.
7. The compound according to claim 1, which is selected from
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(methylsulfonyl)methyl]phenyl-
}pyrimidin-2-amine,
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(methylsulfonyl)methyl]ph-
enyl}pyrimidin-2-amine,
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-(3-{[(2-methoxyethyl)sulfonyl-
]methyl}phenyl) pyrimidin-2-amine,
4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(tert-butylsulfonyl)methyl]phenyl}-
-5-fluoropyrimidin-2-amine,
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(propan-2-ylsulfonyl)meth-
yl]phenyl}pyrimidin-2-amine,
4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(cyclohexylsulfonyl)methyl]phenyl}-
-5-fluoropyrimidin-2-amine,
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(propan-2-ylsulfonyl)methyl]p-
henyl}pyrimidin-2-amine,
2-[(3-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)-
sulfonyl]ethanol,
4-(3,4-Dihydro-2H-chromen-8-yl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phe-
nyl}pyrimidin-2-amine,
N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-4-(3,4-dihydro-2H-chromen-8-yl)-
-5-fluoropyrimidin-2-amine,
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-fluoro-5-[(methylsulfonyl)-
methyl]phenyl}pyrimidin-2-amine,
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(methylsulfonyl)meth-
yl]phenyl}pyrimidin-2-amine,
4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-5-fluoro-N-{3-[(methylsulfonyl)methy-
l]phenyl}pyrimidin-2-amine,
N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyp-
henyl)pyrimidin-2-amine,
N-{3-[(Benzylsulfonyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl-
)pyrimidin-2-amine,
5-Fluoro-4-[4-fluoro-2-(pyridin-3-ylmethoxy)phenyl]-N-{3-[(methylsulfonyl-
)-methyl]phenyl}pyrimidin-2-amine,
5-Fluoro-4-{2-fluoro-4-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(methylsulfonyl-
)-methyl]phenyl}pyrimidin-2-amine,
5-Fluoro-4-{2-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-N-{3-[(methylsulfonyl-
)-methyl]phenyl}pyrimidin-2-amine, or their salts, solvates or
salts of solvates.
8. A method for the treatment and/or prophylaxis of a
hyper-proliferative disorder, virally induced infectious disease or
a cardiovascular disease comprising administering to a patient in
need thereof a pharmaceutically effective amount of a compound
according to claim 1.
9. A method for the treatment and/or prophylaxis of lung
carcinomas, prostate carcinomas, cervical carcinomas, colorectal
carcinomas, melanomas or ovarian carcinomas comprising
administering to a patient in need thereof a pharmaceutically
effective amount of a compound according to claim 1.
10. A pharmaceutical combination comprising a compound according to
claim 1 in combination with at least one further active
ingredients.
11. A pharmaceutical composition comprising a compound according to
claim 1 in combination with an inert, nontoxic, pharmaceutically
suitable adjuvant.
12. (canceled)
13. (canceled)
14. A method for the preparation of a compound of formula (I)
according to claim 1, in which method a compound of formula (3)
##STR00091## in which R.sup.2 is as defined in claim 1, is reacted
with a compound of formula (4) ##STR00092## in which R.sup.1,
R.sup.3 and R.sup.4 are as defined in claim 1, thus providing a
compound of general formula (I), which is optionally reacted with
the corresponding (i) solvents and/or (ii) bases or acids to form a
solvate, salt and/or solvate of a salt of the compound of formula
(I).
Description
[0001] The present invention relates to disubstituted
5-fluoro-pyrimidines of general formula (I) as described and
defined herein, and methods for their preparation, their use for
the treatment and/or prophylaxis of disorders, in particular of
hyper-proliferative disorders and/or virally induced infectious
diseases and/or of cardiovascular diseases. The invention further
relates to intermediate compounds useful in the preparation of said
compounds of general formula (I).
[0002] The family of cyclin-dependent kinase (CDK) proteins
consists of members that are key regulators of the cell division
cycle (cell cycle CDK's), that are involved in regulation of gene
transcription (transcriptional CDK's), and of members with other
functions. CDKs require for activation the association with a
regulatory cyclin subunit. The cell cycle CDKs CDK1/cyclin B,
CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, and CDK6/cyclinD get
activated in a sequential order to drive a cell into and through
the cell division cycle. The transcriptional CDKs CDK9/cyclin T and
CDK7/cyclin H regulate the activity of RNApolymerase II via
phosphorylation of the carboxy-terminal domain (CTD). Positive
transcription factor b (P-TEFb) is a heterodimer of CDK9 and one of
four cyclin partners, cyclin T1, cyclin K, cyclin T2a or T2b.
[0003] Whereas CDK9 (NCBI GenBank Gene ID 1025) is exclusively
involved in transcriptional regulation, CDK7 in addition
participates in cell cycle regulation as CDK-activating kinase
(CAK).
[0004] Transcription of genes by RNA polymerase II is initiated by
assembly of the pre-initiation complex at the promoter region and
phosphorylation of Ser 5 and Ser 7 of the CTD by CDK7/cyclin H. For
a major fraction of genes RNA polymerase II stops mRNA
transcription after it moved 20-40 nucleotides along the DNA
template. This promoter-proximal pausing of RNA polymerase II is
mediated by negative elongation factors and is recognized as a
major control mechanism to regulate expression of rapidly induced
genes in response to a variety of stimuli (Cho et al., Cell Cycle
9, 1697, 2010). P-TEFb is crucially involved in overcoming
promoter-proximal pausing of RNA polymerase II and transition into
a productive elongation state by phosphorylation of Ser 2 of the
CTD as well as by phosphorylation and inactivation of negative
elongation factors.
[0005] Activity of P-TEFb itself is regulated by several
mechanisms. About half of cellular P-TEFb exists in an inactive
complex with 7SK small nuclear RNA (7SK snRNA), La-related protein
7 (LARP7/PIP7S) and hexamethylene bis-acetamide inducible proteins
1/2 (HEXIM1/2, He et al., Mol Cell 29, 588, 2008). The remaining
half of P-TEFb exists in an active complex containing the
bromodomain protein Brd4 (Yang et al., Mol Cell 19, 535, 2005).
Brd4 recruits P-TEFb through interaction with acetylated histones
to chromatin areas primed for gene transcription. Through
alternately interacting with its positive and negative regulators,
P-TEFb is maintained in a functional equilibrium: P-TEFb bound to
the 7SK snRNA complex represents a reservoir from which active
P-TEFb can be released on demand of cellular transcription and cell
proliferation (Zhou & Yik, Microbiol Mol Biol Rev 70, 646,
2006). Furthermore, the activity of P-TEFb is regulated by
posttranslational modifications including
phosphorylation/de-phosphorylation, ubiquitination, and acetylation
(reviewed in Cho et al., Cell Cycle 9, 1697, 2010).
[0006] Deregulated activity of CDK9 kinase activity of the P-TEFb
heterodimer is associated with a variety of human pathological
settings such as hyper-proliferative diseases (e.g. cancer),
virally induced infectious diseases or cardiovascular diseases:
[0007] Cancer is regarded as a hyper-proliferative disorder
mediated by a disbalance of proliferation and cell death
(apoptosis). High levels of anti-apoptotic Bcl-2-family proteins
are found in various human tumors and account for prolonged
survival of tumor cells and therapy resistance. Inhibition of
P-TEFb kinase activity was shown to reduce transcriptional activity
of RNA polymerase II leading to a decline of short-lived
anti-apoptotic proteins, especially Mcl-1 and XIAP, reinstalling
the ability of tumor cells to undergo apoptosis. A number of other
proteins associated with the transformed tumor phenotype (such as
Myc, NF-kB responsive gene transcripts, mitotic kinases) are either
short-lived proteins or are encoded by short-lived transcripts
which are sensitive to reduced RNA polymerase II activity mediated
by P-TEFb inhibition (reviewed in Wang & Fischer, Trends
Pharmacol Sci 29, 302, 2008).
[0008] Many viruses rely on the transcriptional machinery of the
host cell for the transcription of their own genome. In case of
HIV-1, RNA polymerase II gets recruited to the promoter region
within the viral LTR's. The viral transcription activator (Tat)
protein binds to nascent viral transcripts and overcomes
promoter-proximal RNA polymerase II pausing by recruitment of
P-TEFb which in turn promotes transcriptional elongation.
Furthermore, the Tat protein increases the fraction of active
P-TEFb by replacement of the P-TEFb inhibitory proteins HEXIM1/2
within the 7SK snRNA complex. Recent data have shown that
inhibition of the kinase activity of P-TEFb is sufficient to block
HIV-1 repliction at kinase inhibitor concentrations that are not
cytotoxic to the host cells (reviewed in Wang & Fischer, Trends
Pharmacol Sci 29, 302, 2008). Similarly, recruitment of P-TEFb by
viral proteins has been reported for other viruses such as B-cell
cancer-associated Epstein-Barr virus, where the nuclear antigen
EBNA2 protein interacts with P-TEFb (Bark-Jones et al., Oncogene,
25, 1775, 2006), and the human T-lymphotropic virus type 1
(HTLV-1), where the transcriptional activator Tax recruits P-TEFb
(Zhou et al., J Virol. 80, 4781, 2006).
[0009] Cardiac hypertrophy, the heart's adaptive response to
mechanical overload and pressure (hemodynamic stress e.g.
hypertension, myocardial infarction), can lead, on a long term, to
heart failure and death. Cardiac hypertrophy was shown to be
associated with increased transcriptional activity and RNA
polymerase II CTD phosphorylation in cardiac muscle cells. P-TEFb
was found to be activated by dissociation from the inactive 7SK
snRNA/HEXIM1/2 complex. These findings suggest pharmacological
inhibition of P-TEFb kinase activity as a therapeutic approach to
treat cardiac hypertrophy (reviewed in Dey et al., Cell Cycle 6,
1856, 2007).
[0010] In summary, multiple lines of evidence suggest that
selective inhibition of the CDK9 kinase activity of the P-TEFb
heterodimer (=CDK9 and one of four cyclin partners, cyclin T1,
cyclin K, cyclin T2a or T2b) represents an innovative approach for
the treatment of diseases such as cancer, viral diseases, and/or
diseases of the heart. CDK9 belongs to a family of at least 13
closely related kinases of which the subgroup of the cell cycle
CDK's fulfills multiple roles in regulation of cell proliferation.
Thus, co-inhibition of cell cycle CDKs (e.g. CDK1/cyclin B,
CDK2/cyclin A, CDK2/cyclinE, CDK4/cyclinD, CDK6/cyclinD) and of
CDK9, is expected to impact normal proliferating tissues such as
intestinal mucosa, lymphatic and hematopoietic organs, and
reproductive organs. To maximize the therapeutic margin of CDK9
kinase inhibitors, molecules with high selectivity towards CDK9 are
required.
[0011] CDK inhibitors in general as well as CDK9 inhibitors are
described in a number of different publications:
[0012] WO2008129070 and WO2008129071 both describe 2,4
disubstituted aminopyrimidines as CDK inhibitors in general. It is
also asserted that some of these compounds may act as selective
CDK9 inhibitors (WO2008129070) and as CDK5 inhibitors
(WO2008129071), respectively, but no specific CDK9 IC.sub.50
(WO2008129070) or CDK5 IC.sub.50 (WO2008129071) data is presented.
These compounds do not contain a fluoro atom in 5-position of the
pyrimidine core.
[0013] WO2008129080 discloses 4,6 disubstituted aminopyrimidines
and demonstrates that these compounds show an inhibitory effect on
the protein kinase activity of various protein kinases, such as
CDK1, CDK2, CDK4, CDK5, CDK6 and CDK9, with a preference for CDK9
inhibition (example 80).
[0014] WO2005026129 discloses 4,6 disubstituted aminopyrimidines
and demonstrates that these compounds show an inhibitory effect on
the protein kinase activity of various protein kinases, in
particular CDK2, CDK4, and CDK9.
[0015] WO2011116951 discloses substituted triazine derivatives as
selective CDK9 inhibitors.
[0016] EP1218360 B1, which corresponds to US2004116388A1, U.S. Pat.
No. 7,074,789B2 and WO2001025220A1, describes triazine derivatives
as kinase inhibitors, but does not disclose potent or selective
CDK9 inhibitors.
[0017] WO2008079933 discloses aminopyridine and aminopyrimidine
derivatives and their use as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,
CDK7, CDK8 or CDK9 inhibitors.
[0018] WO2011012661 describes aminopyridine derivatives useful as
CDK inhibitors.
[0019] WO2011026917 discloses carboxamides derived from substituted
4-phenylpyridine-2-amines as inhibitors of CDK9.
[0020] WO2012066065 discloses phenyl-heterorayl amines as
inhibitors of CDK9. A selectivity towards CDK9 over other CDK
isoforms is preferred, however disclosure of CDK-inhibition data is
confined to CDK 9. No bicyclic ring systems are disclosed attached
to the C4 position of the pyrimidine core. Within the group
attached to C4 of the pyrimidine core, alkoxy phenyls can be
regarded as encompassed, but there is no suggestion for a specific
substitution pattern characterised by a fluoro atom attached to C5
of the pyrimidine ring, and an aniline at C2 of the pyrimidine,
featuring a substituted sulfonyl-methylene group in meta position.
Compounds shown in the examples typically feature a substituted
cycloalkyl group as R.sup.1 but no phenyl.
[0021] WO2012066070 discloses 3-(aminoaryl)-pyridine compounds as
inhibitors of CDK9. The biaryl core mandatorily consists of two
heteroaromatic rings.
[0022] WO2012101062 discloses substituted bi-heteroaryl compounds
featuring a 2-aminopyridine core as inhibitors of CDK9. The biaryl
core mandatorily consists of two heteroaromatic rings.
[0023] WO2012101063 discloses carboxamides derived from substituted
4-(heteroaryl)-pyridine-2-amines as inhibitors of CDK9.
[0024] WO 2012101064 discloses N-acyl pyrimidine biaryl compounds
as inhibitors of CDK9.
[0025] WO 2012101065 discloses pyrimidine biaryl compounds as
inhibitors of CDK9. The biaryl core mandatorily consists of two
heteroaromatic rings.
[0026] WO 2012101066 discloses pyrimidine biaryl compounds as
inhibitors of CDK9. Substitution R.sup.1 of the amino group
attached to the heteroaromatic core is confined to non-aromatic
groups but does not cover substituted phenyls. Furthermore, the
biaryl core mandatorily consists of two heteroaromatic rings.
[0027] Wang et al. (Chemistry & Biology 17, 1111-1121, 2010)
describe 2-anilino-4-(thiazol-5-yl)pyrimidine transcriptional CDK
inhibitors, which show anticancer activity in animal models.
[0028] WO2004009562 discloses substituted triazine kinase
inhibitors. For selected compounds CDK1 and CDK4 test data, but no
CDK9 data is presented.
[0029] WO2004072063 describes heteroaryl (pyrimidine, triazine)
substituted pyrroles as inhibitors of protein kinases such as ERK2,
GSK3, PICA or CDK2.
[0030] WO2010009155 discloses triazine and pyrimidine derivatives
as inhibitors of histone deacetylase and/or cyclin dependent
kinases (CDKs). For selected compounds CDK2 test data is
described.
[0031] WO2003037346 (corresponding to U.S. Pat. No. 7,618,968B2,
U.S. Pat. No. 7,291,616B2, US2008064700A1, US2003153570A1) relates
to aryl triazines and uses thereof, including to inhibit
lysophosphatidic acid acyltransferase beta (LPAAT-beta) activity
and/or proliferation of cells such as tumor cells.
[0032] WO2008025556 describes carbamoyl sulfoximides having a
pyrimidine core, which are useful as kinase inhibitors. No CDK9
data is presented. No molecules are exemplified, which possess a
fluoropyrimidine core.
[0033] WO2002066481 describes pyrimidine derivatives as cyclin
dependent kinase inhibitors. CDK9 is not mentioned and no CDK9 data
is presented.
[0034] WO2008109943 concerns phenyl aminopyri(mi)dine compounds and
their use as kinase inhibitors, in particular as JAK2 kinase
inhibitors. The specific examples mainly focus on compounds having
a pyrimidine core.
[0035] WO2009032861 describes substituted pyrimidinyl amines as JNK
kinase inhibitors. The specific examples mainly focus on compounds
having a pyrimidine core.
[0036] WO2011046970 concerns amino-pyrimidine compounds as
inhibitors of TBKL and/or IKK epsilon. The specific examples mainly
focus on compounds having a pyrimidine core.
[0037] Despite the fact that various inhibitors of CDKs are known,
there remains a need for selective CDK9 inhibitors to be used for
the treatment of diseases such as hyper-proliferative diseases,
viral diseases, and/or diseases of the heart, which offer one or
more advantages over the compounds known from prior art, such as:
[0038] improved activity and/or efficacy [0039] beneficial kinase
selectivity profile according to the respective therapeutic need
[0040] improved side effect profile, such as fewer undesired side
effects, lower intensity of side effects, or reduced (cyto)toxicity
[0041] improved physicochemical properties, such as solubility in
water and body fluids [0042] improved pharmacokinetic properties,
allowing e.g. for dose reduction or an easier dosing scheme [0043]
easier drug substance manufacturing e.g. by shorter synthetic
routes or easier purification.
[0044] A particular object of the invention is to provide CDK9
kinase inhibitors which, compared to the compounds known from prior
art, show an increased selectivity for CDK9/Cyclin T1 as compared
to CDK2/Cyclin E.
[0045] Another object of the invention is to provide CDK9 kinase
inhibitors which show an increased potency to inhibit CDK9 activity
(demonstrated by a lower IC.sub.50 value for CDK9/Cyclin T1)
compared to the compounds known from prior art.
[0046] Another object of the invention is to provide CDK9 kinase
inhibitors which show an increased potency to inhibit CDK9 activity
at high ATP concentrations compared to the compounds known from
prior art.
[0047] Another object of the invention is to provide CDK9 kinase
inhibitors, which show an improved anti-proliferative activity in
tumor cell lines such as HeLa compared to the compounds known from
prior art.
[0048] Further, it is also an object of the present invention to
provide CDK9 kinase inhibitors, which, compared to the compounds
known from prior art, are highly selective for CDK9/Cyclin T1 as
compared to CDK2/Cyclin E, and/or which show an increased potency
to inhibit CDK9 activity and/or which show an improved
anti-proliferative activity in tumor cell lines such as HeLa and/or
which show an increased potency to inhibit CDK9 activity at high
ATP concentrations compared to the compounds known from prior
art.
[0049] The present invention relates to compounds of general
formula (I)
##STR00001##
wherein [0050] R.sup.1 represents a group selected from
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-,
phenyl, heteroraryl, phenyl-C.sub.1-C.sub.3-alkyl- or
heteroaryl-C.sub.1-C.sub.3-alkyl-, [0051] wherein said group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of hydroxy,
cyano, halogen, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines; [0052] R.sup.2 represents a group selected from
[0052] ##STR00002## [0053] R.sup.3, R.sup.4 represent,
independently from each other, a group selected from a hydrogen
atom, fluoro atom, chloro atom, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-; [0054] R.sup.5 represents a group
selected from [0055] a) a C.sub.1-C.sub.6-alkyl group, which is
optionally substituted with one or two or three substituents,
identically or differently, selected from halogen, hydroxy,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,
wherein said C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl or
heteroaryl group is optionally substituted with one, two or three
substituents, identically or differently, selected from halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0056]
b) a C.sub.3-C.sub.7-cycloalkyl- group, which is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, hydroxy,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-; [0057] c) a
heterocyclyl-group, which is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of halogen, hydroxy, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-; [0058] d) a
phenyl group, which is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group of halogen, hydroxy, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0059] e) a
heteroaryl group, which is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of halogen, hydroxy, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0060] f) a
phenyl-C.sub.1-C.sub.3-alkyl-group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0061] g) a
heteroaryl-C.sub.1-C.sub.3-alkyl-group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0062] h) a
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl-group, which
C.sub.3-C.sub.6-cycloalkyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0063]
i) a heterocyclyl-C.sub.1-C.sub.3-alkyl-group, which heterocyclyl
group is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0064]
j) phenyl-cyclopropyl-group, which phenyl group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, hydroxy, NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-; [0065] k) a heteroaryl-cyclopropyl-group,
which heteroaryl group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group of halogen, hydroxy, NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0066]
R.sup.6, R.sup.7 represent, independently from each other, a group
selected from a hydrogen atom, fluoro atom, chloro atom,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; or
their salts, solvates or salts of solvates.
[0067] Compounds according to the invention are the compounds of
the formula (I) and the salts, solvates and solvates of the salts
thereof, the compounds of the hereinafter recited formula which are
encompassed by formula (I) and the salts, solvates and solvates of
the salts thereof, and the compounds which are encompassed by
formula (I) and are mentioned hereinafter as exemplary embodiments
and the salts, solvates and solvates of the salts thereof, where
the compounds which are encompassed by formula (I) and are
mentioned hereinafter are not already salts, solvates and solvates
of the salts.
[0068] The compounds according to the invention may, depending on
their structure, exist in stereoisomeric forms (enantiomers,
diastereomers). The invention therefore relates to the enantiomers
or diastereomers and respective mixtures thereof. The
stereoisomerically pure constituents can be isolated in a known
manner from such mixtures of enantiomers and/or diastereomers.
[0069] If the compounds according to the invention can be in
tautomeric forms, the present invention encompasses all tautomeric
forms.
[0070] Further, the compounds of the present invention can exist in
free form, e.g. as a free base, or as a free acid, or as a
zwitterion, or can exist in the form of a salt. Said salt may be
any salt, either an organic or inorganic addition salt,
particularly any physiologically acceptable organic or inorganic
addition salt, customarily used in pharmacy.
[0071] Salts which are preferred for the purposes of the present
invention are physiologically acceptable salts of the compounds
according to the invention. However, salts which are not suitable
for pharmaceutical applications per se, but which, for example, can
be used for the isolation or purification of the compounds
according to the invention, are also comprised.
[0072] The term "physiologically acceptable salt" refers to a
relatively non-toxic, inorganic or organic acid addition salt of a
compound of the present invention, for example, see S. M. Berge, et
al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
[0073] Physiologically acceptable salts of the compounds according
to the invention encompass acid addition salts of mineral acids,
carboxylic acids and sulfonic acids, for example salts of
hydrochloric acid, hydrobromic acid, hydroiodic, sulfuric acid,
bisulfuric acid, phosphoric acid, nitric acid or with an organic
acid, such as formic, acetic, acetoacetic, pyruvic,
trifluoroacetic, propionic, butyric, hexanoic, heptanoic,
undecanoic, lauric, benzoic, salicylic,
2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,
cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic,
nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic,
picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic,
trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic,
benzenesulfonic, para-toluenesulfonic, methansulfonic,
2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid,
citric, tartaric, stearic, lactic, oxalic, malonic, succinic,
malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic,
ascorbic, glucoheptanoic, glycerophosphoric, aspartic,
sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.
[0074] Physiologically acceptable salts of the compounds according
to the invention also comprise salts of conventional bases, such
as, by way of example and by preference, alkali metal salts (for
example sodium and potassium salts), alkaline earth metal salts
(for example calcium and magnesium salts) and ammonium salts
derived from ammonia or organic amines with 1 to 16 C atoms, such
as, by way of example and by preference, ethylamine, diethylamine,
triethylamine, ethyldiisopropylamine, monoethanolamine,
diethanolamine, triethanolamine, dicyclohexylamine,
dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,
arginine, lysine, ethylenediamine, N-methylpiperidine,
N-methylglucamine, dimethylglucamine, ethylglucamine,
1,6-hexadiamine, glucosamine, sarcosine, serinol,
tris(hydroxymethyl)aminomethane, aminopropanediol, Sovak base, and
1-amino-2,3,4-butanetriol. Additionally, basic nitrogen containing
groups may be quaternised with such agents as lower alkylhalides
such as methyl-, ethyl-, propyl-, and butylchlorides, -bromides and
-iodides; dialkylsulfates like dimethyl-, diethyl-, dibutyl- and
diamylsulfates, long chain halides such as decyl-, lauryl-,
myristyl- and stearylchlorides, -bromides and -iodides,
aralkylhalides like benzyl- and phenethylbromides and others.
[0075] The present invention includes all possible salts of the
compounds of the present invention as single salts, or as any
mixture of said salts, in any ratio.
[0076] Solvates is the term used for the purposes of the invention
for those forms of the compounds according to the invention which
form a complex with solvent molecules by coordination in the solid
or liquid state. Hydrates are a special form of solvates in which
the coordination takes place with water. Hydrates are preferred as
solvates within the scope of the present invention.
[0077] The invention also includes all suitable isotopic variations
of a compound of the invention. An isotopic variation of a compound
of the invention is defined as one in which at least one atom is
replaced by an atom having the same atomic number but an atomic
mass different from the atomic mass usually or predominantly found
in nature. Examples of isotopes that can be incorporated into a
compound of the invention include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine
and iodine, such as .sup.2H (deuterium), .sup.3H (tritium),
.sup.13C, .sup.14C, .sup.15N, .sup.17O, .sup.18O, .sup.32P,
.sup.33P, .sup.33S, .sup.34S, .sup.35S, .sup.36S, .sup.18F,
.sup.36Cl, .sup.82Br, .sup.123I, .sup.124I, .sup.129I and
.sup.131I, respectively. Certain isotopic variations of a compound
of the invention, for example, those in which one or more
radioactive isotopes such as .sup.3H or .sup.14C are incorporated,
are useful in drug and/or substrate tissue distribution studies.
Tritiated and carbon-14, i.e., .sup.14C, isotopes are particularly
preferred for their ease of preparation and detectability. Further,
substitution with isotopes such as deuterium may afford certain
therapeutic advantages resulting from greater metabolic stability,
for example, increased in vivo half-life or reduced dosage
requirements and hence may be preferred in some circumstances.
Isotopic variations of a compound of the invention can generally be
prepared by conventional procedures known by a person skilled in
the art such as by the illustrative methods or by the preparations
described in the examples hereafter using appropriate isotopic
variations of suitable reagents.
[0078] In addition, the present invention also encompasses prodrugs
of the compounds according to the invention. The term "prodrugs"
encompasses compounds which themselves may be biologically active
or inactive, but are converted (for example by metabolism or
hydrolysis) to compounds according to the invention during their
residence time in the body.
[0079] For the purposes of the present invention, the substituents
have the following meaning, unless otherwise specified:
[0080] The term "halogen atom" or "halo" represents fluorine,
chlorine, bromine and iodine, particularly chlorine or fluorine,
preferably fluorine.
[0081] The term "alkyl" represents a linear or branched alkyl
radical having the number of carbon atoms specifically indicated,
e.g. C.sub.1-C.sub.10 one, two, three, four, five, six, seven,
eight, nine or ten carbon atoms, e.g. methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, hexyl, heptyl, octyl, nonyl-, decyl-, 2-methylbutyl,
1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl,
1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,
1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl,
1,3-dimethylbutyl, or 1,2-dimethylbutyl. If the number of carbon
atoms is not specifically indicated the term "alkyl" represents a
linear or branched alkyl radical having, as a rule, 1 to 9,
particularly 1 to 6, preferably 1 to 4 carbon atoms. Particularly,
the alkyl group has 1, 2, 3, 4, 5 or 6 carbon atoms
("C.sub.1-C.sub.6-alkyl"), e.g. methyl, ethyl, n-propyl-,
isopropyl, n-butyl, tert-butyl, pentyl, isopentyl, hexyl,
2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,
neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,
2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,
2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl.
Preferably, the alkyl group has 1, 2 or 3 carbon atoms
("C.sub.1-C.sub.3-alkyl"), methyl, ethyl, n-propyl or
isopropyl.
[0082] The term "C.sub.2-C.sub.3-alkenyl" is to be understood as
preferably meaning a linear or branched, monovalent hydrocarbon
group, which contains one double bond, and which has 2 or 3 carbon
atoms ("C.sub.2-C.sub.3-alkenyl"). Said alkenyl group is, for
example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl or
isopropenyl group.
[0083] The term "C.sub.2-C.sub.3-alkynyl" is to be understood as
preferably meaning a linear, monovalent hydrocarbon group which
contains one triple bond, and which contains 2 or 3 carbon atoms.
Said C.sub.2-C.sub.3-alkynyl group is, for example, ethynyl,
prop-1-ynyl or prop-2-ynyl group.
[0084] The term "C.sub.3-C.sub.7-cycloalkyl" is to be understood as
preferably meaning a saturated, monovalent, monocyclic hydrocarbon
ring which contains 3, 4, 5, 6 or 7 carbon atoms. Said
C.sub.3-C.sub.7-cycloalkyl group is for example, a monocyclic
hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl or cycloheptyl group. Said cycloalkyl ring can
optionally contain one or more double bonds e.g. cycloalkenyl, such
as a cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl or
cycloheptenyl group, wherein the bond between said ring with the
rest of the molecule may be to any carbon atom of said ring, be it
saturated or unsaturated. Particularly, said cycloalkyl group is a
C.sub.4-C.sub.6-cycloalkyl, a C.sub.5-C.sub.6-cycloalkyl or a
cyclohexyl group.
[0085] The term "C.sub.3-C.sub.5-cycloalkyl" is to be understood as
preferably meaning a saturated, monovalent, monocyclic hydrocarbon
ring which contains 3, 4 or 5 carbon atoms. In particular said
C.sub.3-C.sub.5-cycloalkyl group is a monocyclic hydrocarbon ring
such as a cyclopropyl, cyclobutyl or cyclopentyl group. Preferably
said "C.sub.3-C.sub.5-cycloalkyl" group is a cyclopropyl group.
[0086] The term "C.sub.3-C.sub.6-cycloalkyl" is to be understood as
preferably meaning a saturated, monovalent, monocyclic hydrocarbon
ring which contains 3, 4, 5 or 6 carbon atoms. In particular said
C.sub.3-C.sub.5-cycloalkyl group is a monocyclic hydrocarbon ring
such as a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
group.
[0087] The term "C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl-"
group is to be understood as preferably meaning a
C.sub.3-C.sub.6-cycloalkyl group as defined supra, in which one of
the hydrogen atoms is replaced by a C.sub.1-C.sub.3-alkyl group, as
defined supra, that links the
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl- group to the
molecule. Particularly, the
"C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl-" is a
"C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.2-alkyl-", preferably it
is a "C.sub.3-C.sub.6-cycloalkyl-methyl-" group.
[0088] The term "heterocyclyl" is to be understood as meaning a
saturated or partially unsaturated, monovalent, mono- or bicyclic
hydrocarbon ring which contains 3, 4, 5, 6, 7, 8 or 9 carbon atoms
and further containing 1, 2 or 3 heteroatom-containing groups
selected from oxygen, sulfur, nitrogen. Particularly, the term
"heterocyclyl" is to be understood as meaning a "4- to 10-membered
heterocyclic ring".
[0089] The term "a 4- to 10-membered heterocyclic ring" is to be
understood as meaning a saturated or partially unsaturated,
monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4,
5, 6, 7, 8 or 9 carbon atoms, and further containing 1, 2 or 3
heteroatom-containing groups selected from oxygen, sulfur,
nitrogen. A C.sub.3-C.sub.9-heterocyclyl is to be understood as
meaning a heterocyclyl which contains at least 3, 4, 5, 6, 7, 8 or
9 carbon atoms and additionally at least one heteroatom as ring
atoms. Accordingly in case of one heteroatom the ring is 4- to
10-membered, in case of two heteroatoms the ring is 5- to
11-membered and in case of three heteroatoms the ring is 6- to
12-membered.
[0090] Said heterocyclic ring is for example, a monocyclic
heterocyclic ring such as an oxetanyl, azetidinyl,
tetrahydrofuranyl, pyrrolidinyl, 1,3-dioxolanyl, imidazolidinyl,
pyrazolidinyl, oxazolidinyl, isoxazolidinyl, 1,4-dioxanyl,
pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl,
1,3-dithianyl, thiomorpholinyl, piperazinyl, or chinuclidinyl
group. Optionally, said heterocyclic ring can contain one or more
double bonds, e.g. 4H-pyranyl, 2H-pyranyl, 2,5-dihydro-1H-pyrrolyl,
1,3-dioxolyl, 4H-1,3,4-thiadiazinyl, 2,5-dihydrofuranyl,
2,3-dihydrofuranyl, 2,5-dihydrothienyl, 2,3-dihydrothienyl,
4,5-dihydrooxazolyl, 4,5-dihydroisoxazolyl, or 4H-1,4-thiazinyl
group, or, it may be benzo fused.
[0091] Particularly a C.sub.3-C.sub.7-heterocyclyl is to be
understood as meaning a heterocyclyl which contains at least 3, 4,
5, 6, or 7 carbon atoms and additionally at least one heteroatom as
ring atoms. Accordingly in case of one heteroatom the ring is 4- to
8-membered, in case of two heteroatoms the ring is 5- to 9-membered
and in case of three heteroatoms the ring is 6- to 10-membered.
[0092] Particularly a C.sub.3-C.sub.6-heterocyclyl is to be
understood as meaning a heterocyclyl which contains at least 3, 4,
5 or 6 carbon atoms and additionally at least one heteroatom as
ring atoms. Accordingly in case of one heteroatom the ring is 4- to
7-membered, in case of two heteroatoms the ring is 5- to 8-membered
and in case of three heteroatoms the ring is 6- to 9-membered.
[0093] Particularly, the term "heterocyclyl" is to be understood as
being a heterocyclic ring which contains 3, 4 or 5 carbon atoms,
and 1, 2 or 3 of the above-mentioned heteroatom-containing groups
(a "4- to 7-membered heterocyclic ring"), more particularly said
ring can contain 4 or 5 carbon atoms, and 1, 2 or 3 of the
above-mentioned heteroatom-containing groups (a "5- to 7-membered
heterocyclic ring"), more particularly said heterocyclic ring is a
"6-membered heterocyclic ring", which is to be understood as
containing 4 carbon atoms and 2 of the above-mentioned
heteroatom-containing groups or 5 carbon atoms and one of the
above-mentioned heteroatom-containing groups, preferably 4 carbon
atoms and 2 of the above-mentioned heteroatom-containing
groups.
[0094] The term "heterocyclyl-C.sub.1-C.sub.3-alkyl-" group is to
be understood as preferably meaning a heterocyclyl, preferably a 4-
to 7-membered heterocyclic ring, more preferably a 5- to 7-membered
heterocyclic ring, each as defined supra, in which one of the
hydrogen atoms is replaced by a C.sub.1-C.sub.3-alkyl group, as
defined supra, that links the heterocyclyl-C.sub.1-C.sub.3-alkyl-
group to the molecule. Particularly, the
"heterocyclyl-C.sub.1-C.sub.3-alkyl-" is a
"heterocyclyl-C.sub.1-C.sub.2-alkyl-", preferably it is a
heterocyclyl-methyl- group.
[0095] The term "C.sub.1-C.sub.6-alkoxy-" is to be understood as
preferably meaning a linear or branched, saturated, monovalent,
hydrocarbon group of formula --O-alkyl, in which the term "alkyl"
is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy,
n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentyloxy,
iso-pentyloxy, n-hexyloxy group, or an isomer thereof.
Particularly, the "C.sub.1-C.sub.6-alkoxy-" group is a
"C.sub.1-C.sub.4-alkoxy-", a "C.sub.1-C.sub.3-alkoxy-", a methoxy,
ethoxy, or propoxy group, preferably a methoxy, ethoxy or propoxy
group. Further preferred is a "C.sub.1-C.sub.2-alkoxy-" group,
particularly a methoxy or ethoxy group.
[0096] The term "C.sub.1-C.sub.3-fluoroalkoxy-" is to be understood
as preferably meaning a linear or branched, saturated, monovalent,
C.sub.1-C.sub.3-alkoxy- group, as defined supra, in which one or
more of the hydrogen atoms is replaced, identically or differently,
by one or more fluoro atoms. Said C.sub.1-C.sub.3-fluoroalkoxy-
group is, for example a 1,1-difluoromethoxy-, a
1,1,1-trifluoromethoxy-, a 2-fluoroethoxy-, a 3-fluoropropoxy-, a
2,2,2-trifluoroethoxy-, a 3,3,3-trifluoropropoxy- particularly a
"C.sub.1-C.sub.2-fluoroalkoxy-" group.
[0097] The term "alkylamino-" is to be understood as preferably
meaning an alkylamino group with one linear or branched alkyl group
as defined supra. (C.sub.1-C.sub.3)-alkylamino- for example means a
monoalkylamino group with 1, 2 oder 3 carbon atoms,
(C.sub.1-C.sub.6)-alkylamino- with 1, 2, 3, 4, 5 or 6 carbon atoms.
The term "alkylamino-" comprises for example methylamino-,
ethylamino-, n-propylamino-, isopropylamino-, tert.-butylamino-,
n-pentylamino- or n-hexylamino-.
[0098] The term "dialkylamino-" is to be understood as preferably
meaning an alkylamino group having two linear or branched alkyl
groups as defined supra, which are independent from each other.
(C.sub.1-C.sub.3)-dialkylamino- for example represents a
dialkylamino group with two alkyl groups each of them having 1 to 3
carbon atoms per alkyl group. The term "dialkylamino-" comprises
for example: N,N-Dimethylamino-, N,N-Diethylamino-,
N-Ethyl-N-methylamino-, N-Methyl-N-n-propylamino-,
N-Isopropyl-N-n-propylamino-, N-t-Butyl-N-methylamino-,
N-Ethyl-N-n-pentylamino- and N-n-Hexyl-N-methylamino-.
[0099] The term "cyclic amine" is to be understood as preferably
meaning a cyclic amine group. Suitable cyclic amines are especially
azetidine, pyrrolidine, piperidine, piperazine, 1-methylpiperazine,
morpholine, thiomorpholine, which could be optionally substituted
by one or two methyl groups.
[0100] The term "halo-C.sub.1-C.sub.3-alkyl-" is to be understood
as preferably meaning a linear or branched, saturated, monovalent
hydrocarbon group in which the term "C.sub.1-C.sub.3-alkyl" is
defined supra, and in which one or more hydrogen atoms is replaced
by a halogen atom, identically or differently, i.e. one halogen
atom being independent from another. Particularly, said halogen
atom is fluorine. Preferred halo-C.sub.1-C.sub.3-alkyl- group is a
fluoro-C.sub.1-C.sub.3-alkyl- group, such as for example
--CF.sub.3, --CHF.sub.2, --CH.sub.2F, --CF.sub.2CF.sub.3, or
--CH.sub.2CF.sub.3, preferably it is --CF.sub.3.
[0101] The term "phenyl-C.sub.1-C.sub.3-alkyl-" is to be understood
as preferably meaning a phenyl group, in which one of the hydrogen
atoms is replaced by a C.sub.1-C.sub.3-alkyl group, as defined
supra, that links the phenyl-C.sub.1-C.sub.3-alkyl- group to the
molecule. Particularly, the "phenyl-C.sub.1-C.sub.3-alkyl-" is a
phenyl-C.sub.1-C.sub.2-alkyl-, preferably it is a benzyl-
group.
[0102] The term "heteroaryl" is to be understood as preferably
meaning a monovalent, aromatic ring system having 5, 6, 7, 8, 9,
10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl"
group), particularly 5 (a "5-membered heteroaryl") or 6 (a
"6-membered heteroaryl") or 9 (a "9-membered heteroaryl") or 10
ring atoms (a "10-membered heteroaryl"), and which contains at
least one heteroatom which may be identical or different, said
heteroatom being such as oxygen, nitrogen or sulfur, and can be
monocyclic, bicyclic, or tricyclic, and in addition in each case
can be benzo-condensed. Particularly, heteroaryl is selected from
thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, tetrazolyl etc., and benzo derivatives thereof, such
as, for example, benzofuranyl, benzothienyl, benzoxazolyl,
benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl,
isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
triazinyl, etc., and benzo derivatives thereof, such as, for
example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or
azocinyl, indolizinyl, purinyl, etc., and benzo derivatives
thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl, xanthenyl, or oxepinyl, etc.
Preferably, heteroaryl is selected from monocyclic heteroaryl,
5-membered heteroaryl or 6-membered heteroaryl.
[0103] The term "5-membered heteroaryl" is understood as preferably
meaning a monovalent, aromatic ring system having 5 ring atoms and
which contains at least one heteroatom which may be identical or
different, said heteroatom being such as oxygen, nitrogen or
sulfur. Particularly, "5-membered heteroaryl" is selected from
thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
thiadiazolyl, tetrazolyl.
[0104] The term "6-membered heteroaryl" is understood as preferably
meaning a monovalent, aromatic ring system having 6 ring atoms and
which contains at least one heteroatom which may be identical or
different, said heteroatom being such as oxygen, nitrogen or
sulfur. Particularly, "6-membered heteroaryl" is selected from
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl.
[0105] The term "heteroaryl-C.sub.1-C.sub.3-alkyl-" is to be
understood as preferably meaning a heteroaryl, a 5-membered
heteroaryl or a 6-membered heteroaryl group, each as defined supra,
in which one of the hydrogen atoms is replaced by a
C.sub.1-C.sub.3-alkyl group, as defined supra, that links the
heteroaryl-C.sub.1-C.sub.3-alkyl- group to the molecule.
Particularly, the "heteroaryl-C.sub.1-C.sub.3-alkyl-" is a
heteroaryl-C.sub.1-C.sub.2-alkyl-, a
pyridinyl-C.sub.1-C.sub.3-alkyl-, a pyridinylmethyl-, a
pyridinylethyl-, a pyridinylpropyl-, a
pyrimidinyl-C.sub.1-C.sub.3-alkyl-, a pyrimidinylmethyl-, a
pyrimidinylethyl-, a pyrimidinylpropyl-, preferably a
pyridinylmethyl- or a pyridinylethyl- or a pyrimidinylethyl- or a
pyrimidinylpropyl- group.
[0106] The term "C.sub.1-C.sub.10", as used throughout this text,
e.g. in the context of the definition of "C.sub.1-C.sub.10-alkyl"
is to be understood as meaning an alkyl group having a finite
number of carbon atoms of 1 to 10, i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9
or 10 carbon atoms. It is to be understood further that said term
"C.sub.1-C.sub.10" is to be interpreted as any sub-range comprised
therein, e.g. C.sub.1-C.sub.10, C.sub.1-C.sub.9, C.sub.1-C.sub.8,
C.sub.1-C.sub.7, C.sub.1-C.sub.6, C.sub.1-C.sub.5, C.sub.1-C.sub.4,
C.sub.1-C.sub.3, C.sub.1-C.sub.2, C.sub.2-C.sub.10,
C.sub.2-C.sub.9, C.sub.2-C.sub.8, C.sub.2-C.sub.7, C.sub.2-C.sub.6,
C.sub.2-C.sub.5, C.sub.2-C.sub.4, C.sub.2-C.sub.3,
C.sub.3-C.sub.10, C.sub.3-C.sub.9, C.sub.3-C.sub.8,
C.sub.3-C.sub.7, C.sub.3-C.sub.6, C.sub.3-C.sub.5, C.sub.3-C.sub.4,
C.sub.4-C.sub.10, C.sub.4-C.sub.9, C.sub.4-C.sub.8,
C.sub.4-C.sub.7, C.sub.4-C.sub.6, C.sub.4-C.sub.5,
C.sub.5-C.sub.10, C.sub.5-C.sub.9, C.sub.5-C.sub.8,
C.sub.5-C.sub.7, C.sub.5-C.sub.6, C.sub.6-C.sub.10,
C.sub.6-C.sub.9, C.sub.6-C.sub.8, C.sub.6-C.sub.7,
C.sub.7-C.sub.10, C.sub.7-C.sub.9, C.sub.7-C.sub.8,
C.sub.8-C.sub.10, C.sub.8-C.sub.9, C.sub.9-C.sub.10.
[0107] Similarly, as used herein, the term "C.sub.1-C.sub.6", as
used throughout this text, e.g. in the context of the definition of
"C.sub.1-C.sub.6-alkyl", "C.sub.1-C.sub.6-alkoxy" is to be
understood as meaning an alkyl group having a finite number of
carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms. It is
to be understood further that said term "C.sub.1-C.sub.6" is to be
interpreted as any sub-range comprised therein, e.g.
C.sub.1-C.sub.6, C.sub.1-C.sub.5, C.sub.1-C.sub.4, C.sub.1-C.sub.3,
C.sub.1-C.sub.2, C.sub.2-C.sub.6, C.sub.2-C.sub.5, C.sub.2-C.sub.4,
C.sub.2-C.sub.3, C.sub.3-C.sub.6, C.sub.3-C.sub.5, C.sub.3-C.sub.4,
C.sub.4-C.sub.6, C.sub.4-C.sub.5, C.sub.5-C.sub.6.
[0108] Similarly, as used herein, the term "C.sub.1-C.sub.3", as
used throughout this text, e.g. in the context of the definition of
"C.sub.1-C.sub.3-alkyl", "C.sub.1-C.sub.3-alkoxy" or
"C.sub.1-C.sub.3-fluoroalkoxy" is to be understood as meaning an
alkyl group having a finite number of carbon atoms of 1 to 3, i.e.
1, 2 or 3 carbon atoms. It is to be understood further that said
term "C.sub.1-C.sub.3" is to be interpreted as any sub-range
comprised therein, e.g. C.sub.1-C.sub.3, C.sub.1-C.sub.2,
C.sub.2-C.sub.3.
[0109] Further, as used herein, the term "C.sub.3-C.sub.6", as used
throughout this text, e.g. in the context of the definition of
"C.sub.3-C.sub.6-cycloalkyl", is to be understood as meaning a
cycloalkyl group having a finite number of carbon atoms of 3 to 6,
i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that
said term "C.sub.3-C.sub.6" is to be interpreted as any sub-range
comprised therein, e.g. C.sub.3-C.sub.6, C.sub.3-C.sub.5,
C.sub.3-C.sub.4, C.sub.4-C.sub.6, C.sub.4-C.sub.5,
C.sub.5-C.sub.6.
[0110] Further, as used herein, the term "C.sub.3-C.sub.7", as used
throughout this text, e.g. in the context of the definition of
"C.sub.3-C.sub.7-cycloalkyl", is to be understood as meaning a
cycloalkyl group having a finite number of carbon atoms of 3 to 7,
i.e. 3, 4, 5, 6 or 7 carbon atoms, particularly 3, 4, 5 or 6 carbon
atoms. It is to be understood further that said term
"C.sub.3-C.sub.7" is to be interpreted as any sub-range comprised
therein, e.g. C.sub.3-C.sub.7, C.sub.3-C.sub.6, C.sub.3-C.sub.5,
C.sub.3-C.sub.4, C.sub.4-C.sub.7, C.sub.4-C.sub.6, C.sub.4-C.sub.5,
C.sub.5-C.sub.7, C.sub.5-C.sub.6, C.sub.6-C.sub.7.
[0111] A symbol at a bond denotes the linkage site in the
molecule.
[0112] As used herein, the term "one or more times", e.g. in the
definition of the substituents of the compounds of the general
formulae of the present invention, is understood as meaning one,
two, three, four or five times, particularly one, two, three or
four times, more particularly one, two or three times, even more
particularly one or two times.
[0113] Where the plural form of the word compounds, salts,
hydrates, solvates and the like, is used herein, this is taken to
mean also a single compound, salt, isomer, hydrate, solvate or the
like.
[0114] In another embodiment the present invention concerns
compounds of general formula (I), wherein
##STR00003##
wherein [0115] R.sup.1 represents a group selected from
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl or
phenyl-C.sub.1-C.sub.3-alkyl-, wherein said group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of hydroxy or
C.sub.1-C.sub.6-alkoxy, [0116] R.sup.2 represents a group selected
from
[0116] ##STR00004## [0117] R.sup.3, R.sup.4 represent,
independently from each other, a group selected from a hydrogen or
fluoro atom; [0118] R.sup.5 represents a group selected from [0119]
a) a C.sub.1-C.sub.6-alkyl group, which is optionally substituted
with one or two or three substituents, identically or differently,
selected from halogen, hydroxy, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,
wherein said C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl or
heteroaryl group is optionally substituted with one, two or three
substituents, identically or differently, selected from halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0120]
b) a phenyl-C.sub.1-C.sub.3-alkyl-group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0121] c) a
heteroaryl-C.sub.1-C.sub.3-alkyl-group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0122]
R.sup.6, R.sup.7 represent, independently from each other, a group
selected from a hydrogen atom, fluoro atom, chloro atom,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; or
their salts, solvates or salts of solvates.
[0123] In another embodiment the present invention concerns
compounds of general formula (I), wherein [0124] R.sup.1 represents
a group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally
substituted with one or two substituents, identically or
differently, selected from the group of hydroxy,
C.sub.1-C.sub.2-alkoxy-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-; [0125] R.sup.2 represents a group
selected from
[0125] ##STR00005## [0126] R.sup.3 represents a hydrogen atom or a
fluoro atom; [0127] R.sup.4 represents a hydrogen atom or a fluoro
atom; [0128] R.sup.5 represents a group selected from [0129] a) a
C.sub.1-C.sub.6-alkyl group, which is optionally substituted with
one or two or three substituents, identically or differently,
selected from halogen, hydroxy, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,
wherein said C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl or
heteroaryl group is optionally substituted with one, two or three
substituents, identically or differently, selected from halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-;
[0130] b) a phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group
is optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-; [0131] c) a
heteroaryl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-; [0132] d) a
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl- group, which
C.sub.3-C.sub.6-cycloalkyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0133]
e) a heterocyclyl-C.sub.1-C.sub.3-alkyl- group, which heterocyclyl
group is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0134]
f) phenyl-cyclopropyl- group, which phenyl group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, hydroxy,
--NH.sub.2, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-; [0135] g) a heteroaryl-cyclopropyl- group,
which heteroaryl group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group of halogen, hydroxy, --NH.sub.2, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-. [0136]
R.sup.6, R.sup.7 represent, independently from each other, a group
selected from a hydrogen atom, fluoro atom, chloro atom,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; or
their salts, solvates or salts of solvates.
[0137] In another embodiment the present invention concerns
compounds of general formula (I), wherein [0138] R.sup.1 represents
a group selected from C.sub.1-C.sub.4-alkyl-,
C.sub.3-C.sub.6-cycloalkyl or phenyl-C.sub.1-C.sub.2-alkyl-,
wherein said group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group of hydroxy or C.sub.1-C.sub.3-alkoxy, [0139] R.sup.2
represents a group selected from
[0139] ##STR00006## [0140] R.sup.3, R.sup.4 represent,
independently from each other a group selected from a hydrogen or
fluoro atom, [0141] R.sup.5 represents a group selected from [0142]
a) a C.sub.1-C.sub.3-alkyl group, which is optionally substituted
with one or two or three substituents, identically or differently,
selected from halogen, hydroxy, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,
wherein said C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl or
heteroaryl group is optionally substituted with one, two or three
substituents, identically or differently, selected from halogen,
hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0143]
b) a phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0144] c) a
heteroaryl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0145]
R.sup.6, R.sup.7 represent, independently from each other, a group
selected from a hydrogen or fluoro atom or C.sub.1-C.sub.3-alkoxy-,
or their salts, solvates or salts of solvates.
[0146] In another embodiment the present invention concerns
compounds of general formula (I), wherein [0147] R.sup.1 represents
a group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally
substituted with one or two substituents, identically or
differently, selected from the group of hydroxy,
C.sub.1-C.sub.6-alkoxy-; [0148] R.sup.2 represents a group selected
from
[0148] ##STR00007## [0149] R.sup.3 represents a hydrogen atom or
fluoro atom; [0150] R.sup.4 represents a hydrogen atom or a fluoro
atom; [0151] R.sup.5 represents a group selected from [0152] a) a
C.sub.1-C.sub.3-alkyl group, which is optionally substituted with
one or two or three substituents, identically or differently,
selected from halogen, cyano, halo-C.sub.1-C.sub.3-alkyl-; [0153]
b) a phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0154] c) a
heteroaryl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two substituents, identically or
differently, selected from the group of halogen, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0155] d) a
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl- group, which
C.sub.3-C.sub.6-cycloalkyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0156]
e) a heterocyclyl-C.sub.1-C.sub.3-alkyl- group, which heterocyclyl
group is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-; [0157]
f) phenyl-cyclopropyl- group, which phenyl group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0158] g) a
heteroaryl-cyclopropyl- group, which heteroaryl group is optionally
substituted with one or two or three substituents, identically or
differently, selected from the group of halogen, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-; [0159]
R.sup.6, R.sup.7 represent, independently from each other, a group
selected from a hydrogen atom or a fluoro atom; or their salts,
solvates or salts of solvates.
[0160] In a preferred embodiment the present invention concerns
compounds of general formula (I), wherein [0161] R.sup.1 represents
a group selected from C.sub.1-C.sub.6-alkyl-,
C.sub.3-C.sub.5-cycloalkyl-, wherein said group is optionally
substituted with one or two substituents, identically or
differently, selected from the group of hydroxy,
C.sub.1-C.sub.6-alkoxy-; [0162] R.sup.2 represents a group selected
from
[0162] ##STR00008## [0163] R.sup.3 represents a hydrogen atom or
fluoro atom; [0164] R.sup.4 represents a hydrogen atom; [0165]
R.sup.5 represents a group selected from [0166] a) a
C.sub.1-C.sub.3-alkyl group; [0167] b) a
phenyl-C.sub.1-C.sub.3-alkyl- group; [0168] R.sup.6, R.sup.7
represent, independently from each other, a group selected from a
hydrogen atom or fluoro atom; or their salts, solvates or salts of
solvates.
[0169] In another preferred embodiment the present invention
concerns compounds of general formula (I), [0170] R.sup.1
represents a group selected from C.sub.1-C.sub.3-alkyl-,
C.sub.3-C.sub.5-cycloalkyl- or phenyl-C.sub.1-C.sub.2-alkyl-,
wherein said group is optionally substituted with one or two or
three substituents, identically or differently, selected from the
group of hydroxy or methoxy, [0171] R.sup.2 represents a group
selected from
[0171] ##STR00009## [0172] R.sup.3 represents a hydrogen or fluoro
atom, [0173] R.sup.4 represents a hydrogen atom, [0174] R.sup.5
represents a group selected from [0175] a) a C.sub.1-C.sub.3-alkyl
group, [0176] b) a phenyl-C.sub.1-C.sub.3-alkyl- group, which
phenyl group is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of halogen or C.sub.1-C.sub.3-alkoxy-; [0177] c) a
pyridyl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen or
C.sub.1-C.sub.3-alkoxy-; [0178] R.sup.6, R.sup.7 represent,
independently from each other, a group selected from a hydrogen or
fluoro atom, or their salts, solvates or salts of solvates.
[0179] In another preferred embodiment the present invention
concerns compounds of general formula (I), wherein [0180] R.sup.1
represents a group selected from methyl, ethyl, propan-2yl-,
cyclopropyl, tert-butyl-, cyclohexyl, wherein said group is
optionally substituted with one substituent selected from the group
of hydroxy, methoxy-; C.sub.1-C.sub.6-alkoxy-; [0181] R.sup.2
represents a group selected from
[0181] ##STR00010## [0182] R.sup.3 represents a hydrogen atom or
fluoro atom; [0183] R.sup.4 represents a hydrogen atom; [0184]
R.sup.5 represents a group selected from methyl and benzyl; [0185]
R.sup.6, R.sup.7 represent, independently from each other, a group
selected from a hydrogen atom or fluoro atom; or their salts,
solvates or salts of solvates.
[0186] In another embodiment the present invention concerns
compounds of general formula (I), wherein [0187] R.sup.1 represents
a group selected from methyl, ethyl, propan-2yl-, cyclopropyl,
tert-butyl-, cyclohexyl, wherein said group is optionally
substituted with one substituent selected from the group of
hydroxy, methoxy-; C.sub.1-C.sub.6-alkoxy-; [0188] R.sup.2
represents a group selected from 4-fluoro-2-methoxyphenyl-,
2-(benzyloxy)-4-fluorophenyl-, 3,4-dihydro-2H-chromen-8-yl-; [0189]
R.sup.3 represents a hydrogen atom or fluoro atom; [0190] R.sup.4
represents a hydrogen atom; or their salts, solvates or salts of
solvates.
[0191] In another embodiment the present invention concerns
compounds of general formula (I), wherein [0192] R.sup.1 represents
a methyl group; [0193] R.sup.2 represents a group selected from
4-fluoro-2-methoxyphenyl-, 2-(benzyloxy)-4-fluorophenyl-,
3,4-dihydro-2H-chromen-8-yl-; [0194] R.sup.3 represents a hydrogen
atom or fluoro atom; [0195] R.sup.4 represents a hydrogen atom; or
their salts, solvates or salts of solvates.
[0196] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.1 represents a C.sub.1-C.sub.6-alkyl-,
a C.sub.3-C.sub.7-cycloalkyl-, a heterocyclyl-, a phenyl, a
heteroraryl, a phenyl-C.sub.1-C.sub.3-alkyl- or a
heteroaryl-C.sub.1-C.sub.3-alkyl- group, [0197] wherein said group
is optionally substituted with one or two or three substituents,
identically or differently, selected from the group of hydroxy,
cyano, halogen, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.6-alkoxy-, C.sub.1-C.sub.3-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines.
[0198] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.1 represents a C.sub.1-C.sub.3-alkyl-,
a C.sub.3-C.sub.5-cycloalkyl-, a 4- to 7-membered heterocyclic
ring, a phenyl, a heteroraryl, a phenyl-C.sub.1-C.sub.2-alkyl- or a
heteroaryl-C.sub.1-C.sub.2-alkyl- group, [0199] wherein said group
is optionally substituted with one or two or three substituents,
identically or differently, selected from the group of hydroxy,
cyano, halogen, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.3-alkoxy-, C.sub.1-C.sub.2-fluoroalkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines.
[0200] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.1 represents a phenyl or a heteroraryl
group, [0201] wherein said group is optionally substituted with one
or two or three substituents, identically or differently, selected
from the group of hydroxy, cyano, halogen,
halo-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.3-alkoxy-,
C.sub.1-C.sub.2-fluoroalkoxy-, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines.
[0202] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.1 represents a group selected from
methyl, ethyl, propan-2-yl, cyclopropyl, tert-butyl, cyclopentyl,
cyclohexyl or phenyl; [0203] wherein said group is optionally
substituted with one substituent selected from the group of
hydroxyl or methoxy.
[0204] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.1 represents a group selected from
methyl, ethyl, propan-2-yl, tert butyl, cyclopropyl, cyclohexyl or
phenyl; [0205] wherein said group is optionally substituted with
one substituent selected from the group of hydroxyl or methoxy.
[0206] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.1 represents a group selected from
C.sub.1-C.sub.6-alkyl-, C.sub.3-C.sub.7-cycloalkyl or
phenyl-C.sub.1-C.sub.3-alkyl-, [0207] wherein said group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of hydroxy or
C.sub.1-C.sub.6-alkoxy.
[0208] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.1 represents a group selected from
C.sub.1-C.sub.4-alkyl-, C.sub.3-C.sub.6-cycloalkyl or
phenyl-C.sub.1-C.sub.2-alkyl-, [0209] wherein said group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of hydroxy or
C.sub.1-C.sub.3-alkoxy.
[0210] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.1 represents a group selected from
methyl or cyclopropyl.
[0211] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.1 represents a cyclopropyl
group.
[0212] In another preferred embodiment the invention relates to
compounds of formula (I), in which R.sup.1 represents a methyl
group.
[0213] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
##STR00011##
[0214] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
##STR00012##
[0215] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
##STR00013##
[0216] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
##STR00014##
[0217] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
##STR00015##
[0218] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
##STR00016##
[0219] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
##STR00017##
[0220] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.2 represents
##STR00018##
[0221] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
4,5-difluoro-2-methoxyphenyl-; 3,4-difluoro-2-methoxyphenyl-,
4-fluoro-2-methoxyphenyl-, 2-(benzyloxy)-4-fluorophenyl-,
5-fluoro-2-methoxyphenyl-, 2-[(4-fluorobenzyl)oxy]phenyl-,
2-[(3-fluorobenzyl)oxy]phenyl-, 2-[(2-chlorobenzyl)oxy]phenyl-,
2-[(3-chlorobenzyl)oxy]phenyl-,
5-fluoro-2-[(2-fluorobenzyl)oxy]phenyl-,
5-fluoro-2-[(3-fluorobenzyl)oxy]phenyl-, 4-chloro-2-methoxyphenyl-,
3,4-dihydro-2H-chromen-8-yl-.
[0222] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
4,5-difluoro-2-methoxyphenyl-; 4-fluoro-2-methoxyphenyl-,
2-(benzyloxy)-4-fluorophenyl-, 2-[(4-fluorobenzyl)oxy]phenyl-,
2-[(3-fluorobenzyl)oxy]phenyl-, 2-[(3-chlorobenzyl)oxy]phenyl-,
5-fluoro-2-[(3-fluorobenzyl)oxy]phenyl-,
3,4-dihydro-2H-chromen-8-yl-.
[0223] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
4,5-difluoro-2-methoxyphenyl-; 4-fluoro-2-methoxyphenyl-,
2-(benzyloxy)-4-fluorophenyl-, 2-[(4-fluorobenzyl)oxy]phenyl-,
2-[(3-fluorobenzyl)oxy]phenyl-,
5-fluoro-2-[(3-fluorobenzyl)oxy]phenyl-,
3,4-dihydro-2H-chromen-8-yl-.
[0224] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
4-fluoro-2-methoxyphenyl-, 2-(benzyloxy)-4-fluorophenyl-,
2-[(3-fluorobenzyl)oxy]phenyl-,
5-fluoro-2-[(3-fluorobenzyl)oxy]phenyl-,
3,4-dihydro-2H-chromen-8-yl-.
[0225] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
4-fluoro-2-methoxyphenyl-, 2-(benzyloxy)-4-fluorophenyl-,
3,4-dihydro-2H-chromen-8-yl-.
[0226] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.2 represents a group selected from
4-fluoro-2-methoxyphenyl- or 2-(benzyloxy)-4-fluorophenyl-.
[0227] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.2 represents a
4-fluoro-2-methoxyphenyl- group.
[0228] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-.
[0229] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0230] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen, a fluoro or a chloro atom.
[0231] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 and R.sup.4 represent independently
from each other a group selected from a hydrogen or fluoro
atom.
[0232] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a hydrogen or fluoro atom
and R.sup.4 represents a hydrogen atom.
[0233] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a fluoro or a chloro
atom.
[0234] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a group selected from a
hydrogen atom or a fluoro atom.
[0235] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.3 represents a hydrogen atom.
[0236] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.3 represents a fluoro atom.
[0237] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.4 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-.
[0238] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.4 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0239] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.4 represents a group selected from a
hydrogen, a fluoro or a chloro atom.
[0240] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.4 represents a fluoro or a chloro
atom.
[0241] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.4 represents a group selected from a
hydrogen atom or fluoro atom.
[0242] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.4 represents a hydrogen atom.
[0243] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.4 represents a fluoro atom.
[0244] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.6-alkyl
group, which is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of halogen, hydroxy, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.7-cycloalkyl-, C.sub.3-C.sub.7-heterocyclyl-, phenyl,
heteroaryl, [0245] wherein said C.sub.3-C.sub.7-cycloalkyl-,
C.sub.3-C.sub.7-heterocyclyl-, phenyl or heteroaryl group is
optionally substituted with one, two or three substituents,
identically or differently, selected from halogen, hydroxy,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-.
[0246] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.3-alkyl
group, which is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of halogen, hydroxy, --NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.4-C.sub.6-cycloalkyl-, C.sub.3-C.sub.7-heterocyclyl-, phenyl,
heteroaryl, [0247] wherein said C.sub.4-C.sub.6-cycloalkyl-,
C.sub.3-C.sub.7-heterocyclyl-, phenyl or heteroaryl group is
optionally substituted with one, two or three substituents,
identically or differently, selected from halogen, hydroxy,
C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-alkoxy-, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0248] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.6-alkyl
group, which is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,
[0249] wherein said C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-,
phenyl or heteroaryl group is optionally substituted with one, two
or three substituents, identically or differently, selected from
halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0250] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.3-alkyl
group, which is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-,
C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-, phenyl, heteroaryl,
[0251] wherein said C.sub.3-C.sub.7-cycloalkyl-, heterocyclyl-,
phenyl or heteroaryl group is optionally substituted with one, two
or three substituents, identically or differently, selected from
halogen, hydroxy, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
--NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0252] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.3-alkyl
group.
[0253] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.6-alkyl-
group, which is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of halogen atom, C.sub.1-C.sub.3-alkyl-,
C.sub.3-C.sub.6-cycloalkyl-, C.sub.3-C.sub.6-heterocyclyl-, phenyl,
heteroaryl, wherein said C.sub.3-C.sub.6-cycloalkyl-,
C.sub.3-C.sub.6-heterocyclyl-, phenyl- or heteroaryl group is
optionally substituted with one substituent selected from
halogen.
[0254] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.3-alkyl
group, which is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
cyano, halo-C.sub.1-C.sub.3-alkyl-.
[0255] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.3-alkyl-
group, which is substituted with one or two or three substituents,
identically or differently, selected from the group of a halogen
atom.
[0256] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.3-alkyl-
group, which is substituted with one or two or three substituents,
identically or differently, selected from the group of a chloro or
fluoro atom.
[0257] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a C.sub.1-C.sub.3-alkyl-
group, which is substituted with one or two or three substituents
selected from the group of a fluoro atom.
[0258] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a group selected from
--CH.sub.2CH.sub.2CF.sub.3, --CH.sub.2CH.sub.2CF.sub.2CF.sub.3.
[0259] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a group selected from
methyl, (.sup.2H.sub.3)methyl.
[0260] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a methyl group.
[0261] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
C.sub.5-C.sub.6-cycloalkyl- group, which is optionally substituted
with one or two or three substituents, identically or differently,
selected from the group of halogen, hydroxy, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-, C.sub.2-C.sub.3-alkenyl-,
C.sub.2-C.sub.3-alkynyl-.
[0262] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
C.sub.5-C.sub.6-cycloalkyl- group, which is optionally substituted
with one or two or three substituents, identically or differently,
selected from the group of fluoro, chloro, hydroxy, --NH.sub.2,
alkylamino-, dialkylamino-, acetylamino-, N-methyl-N-acetylamino-,
cyclic amines, cyano, C.sub.1-C.sub.2-alkyl-,
halo-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-,
C.sub.1-C.sub.2-alkoxy-, C.sub.2-C.sub.3-alkenyl-,
C.sub.2-C.sub.3-alkynyl-.
[0263] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a cyclopentyl or
cyclohexyl group, which is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of fluoro, chloro, hydroxy, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.2-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-.
[0264] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a cyclohexyl or
cyclopentyl group.
[0265] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
C.sub.3-C.sub.6-cycloalkyl-C.sub.1-C.sub.3-alkyl- group, which
C.sub.3-C.sub.6-cycloalkyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0266] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
C.sub.3-C.sub.6-cycloalkyl-CH.sub.2-- group, which
C.sub.3-C.sub.6-cycloalkyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0267] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.5 represents a cyclohexyl-CH.sub.2--
or cyclopentyl-CH.sub.2-- group, which cyclohexyl or cyclopentyl
group is optionally substituted with one or two or three
substituents, identically or differently, selected from halogen,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0268] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
heterocyclyl-C.sub.1-C.sub.3-alkyl- group, which heterocyclyl group
is optionally substituted with one or two or three substituents,
identically or differently, selected from halogen,
C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0269] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a heterocyclyl-CH.sub.2--
group, which heterocyclyl group is optionally substituted with one
or two or three substituents, identically or differently, selected
from halogen, C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-alkoxy-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-.
[0270] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a 4- to 7-membered
heterocyclic ring, which is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of halogen, hydroxy, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-.
[0271] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a 4- to 7-membered
heterocyclic ring, which is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of halogen, hydroxy, --NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.2-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-,
C.sub.2-C.sub.3-alkenyl-, C.sub.2-C.sub.3-alkynyl-.
[0272] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a phenyl group, which is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-.
[0273] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a phenyl group, which is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.2-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-.
[0274] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a heteroaryl group, which
is optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-.
[0275] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a heteroaryl group, which
is optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.2-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-.
[0276] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-;
--C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-.
[0277] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen or
C.sub.1-C.sub.3-alkoxy-.
[0278] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
phenyl-C.sub.1-C.sub.3-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-.
[0279] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
phenyl-C.sub.1-C.sub.2-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-.
[0280] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
phenyl-C.sub.1-C.sub.2-alkyl- group, which phenyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.2-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-.
[0281] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a benzyl group, which
phenyl group is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of halogen, hydroxy, NH.sub.2, alkylamino-, dialkylamino-,
acetylamino-, N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.2-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-.
[0282] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a benzyl group, which
phenyl group is optionally substituted with one or two or three
substituents, identically or differently, selected from the group
of a fluoro atom, a methyl group
[0283] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a benzyl group, which
phenyl group is optionally substituted with one or two
substituents, identically or differently, selected from the group
of a fluoro or a chloro atom.
[0284] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a benzyl group, which
phenyl group is optionally substituted with one fluoro atom.
[0285] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a benzyl, a
4-fluorobenzyl-, a 4-chlorobenzyl, a 3-fluorobenzyl or a
3-chlorobenzyl group.
[0286] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a phenyl-cyclopropyl-
group, which phenyl group is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of halogen, hydroxy, NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-.
[0287] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a phenyl-cyclopropyl-
group, which phenyl group is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of halogen, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-.
[0288] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a phenyl-cyclopropyl-
group, which phenyl group is optionally substituted with one or two
or three substituents, identically or differently, selected from
the group of a fluoro atom, a methyl group.
[0289] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
heteroaryl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two substituents, identically or
differently, selected from the group of halogen, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-.
[0290] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
heteroaryl-C.sub.1-C.sub.2-alkyl- group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-.
[0291] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
heteroaryl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, --NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy.
[0292] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
pyridyl-C.sub.1-C.sub.3-alkyl- group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen or
C.sub.1-C.sub.3-alkoxy-.
[0293] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
heteroaryl-C.sub.1-C.sub.2-alkyl- group, which heteroaryl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.2-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-.
[0294] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a
pyridyl-C.sub.1-C.sub.2-alkyl- group, which pyridyl group is
optionally substituted with one or two or three substituents,
identically or differently, selected from the group of halogen,
hydroxy, NH.sub.2, alkylamino-, dialkylamino-, acetylamino-,
N-methyl-N-acetylamino-, cyclic amines, cyano,
C.sub.1-C.sub.2-alkyl-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-, C.sub.1-C.sub.2-alkoxy-.
[0295] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a pyridyl-CH.sub.2--
group, which pyridyl group is optionally substituted with one or
two or three substituents, identically or differently, selected
from the group of halogen, C.sub.1-C.sub.2-alkyl-,
halo-C.sub.1-C.sub.2-alkyl-, C.sub.1-C.sub.2-fluoroalkoxy-,
C.sub.1-C.sub.2-alkoxy-.
[0296] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a heteroaryl-cyclopropyl-
group, which heteroaryl group is optionally substituted with one or
two or three substituents, identically or differently, selected
from the group of halogen, hydroxy, NH.sub.2, alkylamino-,
dialkylamino-, acetylamino-, N-methyl-N-acetylamino-, cyclic
amines, cyano, C.sub.1-C.sub.3-alkyl-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-, C.sub.1-C.sub.3-alkoxy-.
[0297] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a heteroaryl-cyclopropyl-
group, which heteroaryl group is optionally substituted with one or
two or three substituents, identically or differently, selected
from the group of halogen, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-.
[0298] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.5 represents a pyridyl-cyclopropyl-
group, which pyridyl group is optionally substituted with one or
two or three substituents, identically or differently, selected
from the group of halogen, cyano, C.sub.1-C.sub.3-alkyl-,
halo-C.sub.1-C.sub.3-alkyl-, C.sub.1-C.sub.3-fluoroalkoxy-,
C.sub.1-C.sub.3-alkoxy-.
[0299] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-.
[0300] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0301] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom.
[0302] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 and R.sup.7 represent, independently
from each other, a group selected from a hydrogen or fluoro atom or
C.sub.1-C.sub.3-alkoxy-.
[0303] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 and R.sup.7 represent, independently
from each other, a group selected from a hydrogen or fluoro
atom.
[0304] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 represents a hydrogen atom.
[0305] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 represents a fluoro atom.
[0306] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.6 is in para position to the
5-fluoro pyrimidine and represents a fluoro atom.
[0307] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.7 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom, C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-alkoxy-, halo-C.sub.1-C.sub.3-alkyl-,
C.sub.1-C.sub.3-fluoroalkoxy-.
[0308] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.7 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom, C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-alkoxy-, halo-C.sub.1-C.sub.2-alkyl-,
C.sub.1-C.sub.2-fluoroalkoxy-.
[0309] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.7 represents a group selected from a
hydrogen atom, fluoro atom, chloro atom.
[0310] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.7 represents a hydrogen atom.
[0311] In another embodiment the invention relates to compounds of
formula (I), in which R.sup.6 represents a fluoro atom and R.sup.7
represents a hydrogen atom.
[0312] In a preferred embodiment the invention relates to compounds
of formula (I), in which R.sup.6 is in para position to the
5-fluoro pyrimidine and represents a fluoro atom and in which
R.sup.7 represents a hydrogen atom.
[0313] It is to be understood that the present invention relates to
any sub-combination within any embodiment of the present invention
of compounds of formula (I), supra.
[0314] More particularly still, the present invention covers
compounds of formula (I) which are disclosed in the Example section
of this text, infra.
[0315] Very specially preferred are combinations of two or more of
the abovementioned preferred embodiments.
[0316] In particular, preferred subjects of the present invention
are the compounds selected from: [0317]
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(methylsulfonyl)methyl]phenyl-
}pyrimidin-2-amine, [0318]
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(methylsulfonyl)methyl]ph-
enyl}pyrimidin-2-amine, [0319]
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-(3-{[(2-methoxyethyl)sulfonyl-
]methyl}phenyl) pyrimidin-2-amine, [0320]
4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(tert-butylsulfonyl)methyl]phenyl}-
-5-fluoropyrimidin-2-amine, [0321]
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(propan-2-ylsulfonyl)meth-
yl]phenyl}pyrimidin-2-amine, [0322]
4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(cyclohexylsulfonyl)methyl]phenyl}-
-5-fluoropyrimidin-2-amine, [0323]
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(propan-2-ylsulfonyl)methyl]p-
henyl}pyrimidin-2-amine, [0324]
2-[(3-{[5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)-
sulfonyl]ethanol, [0325]
4-(3,4-Dihydro-2H-chromen-8-yl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phe-
nyl}pyrimidin-2-amine, [0326]
N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-4-(3,4-dihydro-2H-chromen-8-yl)-
-5-fluoropyrimidin-2-amine, [0327]
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-fluoro-5-[(methylsulfonyl)-
methyl]phenyl}pyrimidin-2-amine, [0328]
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(methylsulfonyl)meth-
yl]phenyl}pyrimidin-2-amine, [0329]
4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-5-fluoro-N-{3-[(methylsulfonyl)methy-
l]phenyl}pyrimidin-2-amine, [0330]
N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyp-
henyl)pyrimidin-2-amine, [0331]
N-{3-[(Benzylsulfonyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl-
)pyrimidin-2-amine, [0332]
5-Fluoro-4-[4-fluoro-2-(pyridin-3-ylmethoxy)phenyl]-N-{3-[(methylsulfonyl-
)-methyl]phenyl}pyrimidin-2-amine, [0333]
5-Fluoro-4-{2-fluoro-4-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(methylsulfonyl-
)-methyl]phenyl}pyrimidin-2-amine, [0334]
5-Fluoro-4-{2-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-N-{3-[(methylsulfonyl-
)-methyl]phenyl}pyrimidin-2-amine, or their salts, solvates or
salts of solvates.
[0335] The abovementioned definitions of radicals which have been
detailed in general terms or in preferred ranges also apply to the
end products of the formula (I) and, analogously, to the starting
materials or intermediates required in each case for the
preparation.
[0336] The invention furthermore relates to a method for the
preparation of the compounds of formula (I) according to the
invention, in which method a compound of formula (3)
##STR00019##
in which R.sup.2 is as defined for the compound of general formula
(I), is reacted with a compound of formula (4)
##STR00020##
in which R.sup.1, R.sup.3 and R.sup.4 are as defined for the
compound of general formula (I), thus providing a compound of
general formula (I) according to the present invention and the
resulting compounds of formula (I) are optionally, if appropriate,
reacted with the corresponding (i) solvents and/or (ii) bases or
acids to the solvates, salts and/or solvates of the salts of the
compounds of formula (I).
[0337] In one embodiment of the present invention the method for
the preparation of the compounds of formula (I) by a coupling
reaction of a compound of formula (3) with a compound of formula
(4) is carried out in an alcohol or in an inert solvent or in
mixtures of such solvents, preferably in 1-butanol or in DMF, THF,
DME, dioxane or mixtures thereof, in the presence of an acid,
preferably in the presence of hydrogen chloride or
4-methylbenzenesulfonic acid. This reaction is carried out at
temperatures ranging from 100.degree. C. to the boiling point of
the solvent, preferably it is carried out at temperatures between
130.degree. C.-160.degree. C. in 1-butanol, more preferably at
about 140.degree. C. in 1-butanol.
[0338] In another embodiment of the present invention the coupling
reaction of a compound of formula (3) with a compound of formula
(4) is done by a Palladium-catalyzed C--N cross-coupling reaction
(for a review on C--N cross-coupling reactions see for example: a)
L. Jiang, S. L. Buchwald in `Metal-Catalyzed Cross-Coupling
Reactions`, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.:
Wiley-VCH: Weinheim, Germany, 2004).
[0339] Preferred is the use of suitable palladium precatalysts
based upon biarylmonphosphines that are easily activated and ensure
the formation of the active mono-ligated Pd(0) complex (see for
examples: a) S. L. Buchwald et al, J. Am. Chem. Soc. 2008, 130,
6686; b) S. L. Buchwald et al, J. Am. Chem. Soc. 2008, 130, 13552).
The reactions are run in the presence of a weak base at elevated
temperatures (see for example: a) S. L: Buchwald et al, Tet. Lett.
2009, 50, 3672).
[0340] Most preferred is the herein described use of
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and potassium
phosphate in toluene and 1-methylpyrrolidin-2-one. The reactions
are preferably run under argon for 3 hours at 130.degree. C. in a
microwave oven or in an oil bath.
[0341] The invention furthermore relates to a method for the
preparation of the compounds of formula (3) according to the
invention, in which method 2-4-dichloro-5-fluoro-pyrimidine
(1),
##STR00021##
is reacted with a compound of formula (2)
##STR00022##
in which R.sup.2 is as defined for the compound of general formula
(I) according to the invention, and R represent, independently from
each other, a hydrogen atom, or a C.sub.1-C.sub.10-alkyl- group or,
alternatively, both R together form a R--R group, which is
--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--, thus providing a compound
of general formula (3) according to the invention and the resulting
compounds of formula (3) according to the invention are optionally,
if appropriate, reacted with the corresponding (i) solvents and/or
(ii) bases or acids to the solvates, salts and/or solvates of the
salts thereof.
[0342] Compounds of general formula (2) can be prepared analogously
to known processes (review: D. G. Hall, Boronic Acids, 2005
WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8
and references cited herein). Further, a wide variety of compounds
of general formula (2) is commercially available.
[0343] The coupling reaction of 2-4-dichloro-5-fluoro-pyrimidine
(1) with compounds of formula (2) is catalyzed by Pd catalysts,
e.g. by Pd(0) catalysts or by Pd(II) catalysts. Examples for Pd(0)
catalysts are tetrakis(triphenylphosphine)palladium(0)
[Pd(PPh.sub.3).sub.4] or tris(dibenzylideneacetone)di-palladium(0)
[Pd.sub.2(dba).sub.3], examples for Pd(II) catalysts
dichlorobis(triphenylphosphine)-palladium(II)
[Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and
triphenylphosphine or
[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (review:
D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co.
KGaA, Weinheim, ISBN 3-527-30991-8 and references cited
therein).
[0344] This reaction is preferably carried out in aprotic or protic
solvents, preferably in a mixture of aprotic and protic solvents,
more preferably in solvents like, for example, 1,2-dimethoxyethane,
dioxane, dimethlyformamid, tetrahydrofuran, or isopropanol with
water (review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag
GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references
cited therein).
[0345] Preferably the reaction is carried out in the presence of a
suitable base, such as for example aqueous potassium carbonate,
aqueous sodium bicarbonate or potassium phosphate (review: D. G.
Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co. KGaA,
Weinheim, ISBN 3-527-30991-8 and references cited therein).
[0346] The reaction is performed at temperatures ranging from room
temperature (=20.degree. C.) to the boiling point of the solvent.
Further on, the reaction can be performed at temperatures above the
boiling point using pressure tubes and a microwave oven. (review:
D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag GmbH & Co.
KGaA, Weinheim, ISBN 3-527-30991-8 and references cited
therein).
[0347] The reaction is preferably completed after 1 to 36 hours of
reaction time.
[0348] The preparation of the compounds of general formula (I)
according to the invention can be illustrated by the following
synthesis scheme 1:
##STR00023##
[0349] 2,4-Dichloro-5-fluoro-pyrimidine (1) is commercially
available.
[0350] A number of compounds of general formula (4) are
commercially available. Further on, the compounds of formula (4)
are known or can be prepared analogously to known processes. For
example, by reaction of suitable benzylchlorides or -bromides of
formula (5) with suitable thiols of formula (6) under basic
conditions the corresponding thioethers of formula (7) can be
prepared (scheme 2, see for example: Sammond et al, Bioorg. Med.
Chem. Lett. 2005, 15, 3519)
##STR00024##
[0351] Oxidation of (7) gives the corresponding sulfones of formula
(8). The oxidation can be prepared analogously to known processes
(scheme 3, see for example: Sammond et al; Bioorg. Med. Chem. Lett.
2005, 15, 3519).
##STR00025##
[0352] Finally, reduction of the nitro group gives the desired
anilines of formula (4). The reduction can be prepared analogously
to known processes (scheme 4, see for example: Sammond et al;
Bioorg. Med. Chem. Lett. 2005, 15, 3519).
##STR00026##
[0353] The compounds according to the invention show a valuable
pharmacological and pharmacokinetic spectrum of action which could
not have been predicted.
[0354] They are therefore suitable for use as medicaments for the
treatment and/or prophylaxis of disorders in humans and
animals.
[0355] Within the scope of the present invention, the term
"treatment" includes prophylaxis.
[0356] The pharmaceutical activity of the compounds according to
the invention can be explained by their action as inhibitors of
CDK9. Thus, the compounds according to the general formula (I) as
well as pharmaceutically acceptable salts thereof are used as
inhibitors for CDK9.
[0357] Furthermore, the compounds according to the invention show a
particularly high potency (demonstrated by a low IC.sub.50 value in
the CDK9/CycT1 assay) for inhibiting CDK9 activity.
[0358] In context of the present invention, the IC.sub.50 value
with respect to CDK9 can be determined by the methods described in
the method section below. Preferably, it is determined according to
Method 1a. ("CDK9/CycT1 kinase assay") described in the Materials
and Method section below.
[0359] Surprisingly it turned out that the compounds according to
the general formula (I) as well as pharmaceutically acceptable
salts thereof selectively inhibit CDK9 in comparison to other
cyclin-dependent protein kinases, preferably in comparison to CDK2.
Thus, the compounds according to the general formula (I) as well as
pharmaceutically acceptable salts thereof are preferably used as
selective inhibitors for CDK9.
[0360] Compounds of the present invention according to general
formula (I) show a significantly stronger CDK9 than CDK2
inhibition.
[0361] In context of the present invention, the IC.sub.50 value
with respect to CDK2 can be determined by the methods described in
the method section below. Preferably, it is determined according to
Method 2. ("CDK2/CycE kinase assay") described in the Materials and
Method section below.
[0362] Further, as compared to the CDK9 inhibitors described in the
prior art, preferred compounds of the present invention according
to general formula (I) show a surprisingly high potency for
inhibiting CDK9 activity at high ATP concentrations, which is
demonstrated by their low IC.sub.50 value in the CDK9/CycT1 high
ATP kinase assay. Thus, these compounds have a lower probability to
be competed out of the ATP-binding pocket of CDK9/CycT1 kinase due
to the high intracellular ATP concentration (R. Copeland et al.,
Nature Reviews Drug Discovery 2006, 5, 730-739). According to this
property the compounds of the present invention are particularly
able to inhibit CDK9/CycT1 within cells for a longer period of time
as compared to classical ATP competitive kinase inhibitors. This
increases the anti-tumor cell efficacy at pharmacokinetic
clearance-mediated declining serum concentrations of the inhibitor
after dosing of a patient or an animal.
[0363] In context of the present invention, the IC.sub.50 value
with respect to CDK9 at high ATP concentrations can be determined
by the methods described in the method section below. Preferably,
it is determined according to Method 1b ("CDK9/CycT1 high ATP
kinase assay") as described in the Materials and Method section
below.
[0364] Further, preferred compounds of the present invention
according to formula (I) show an improved anti-proliferative
activity in tumor cell lines such as HeLa compared to the CDK9
inhibitors described in the prior art. In context of the present
invention, the anti-proliferative activity in tumor cell lines such
as HeLa is preferably determined according to Method 3.
("Proliferation Assay") as described in the Materials and Method
section below.
[0365] Further, preferred compounds of the present invention
according to formula (I) are characterized by improved
pharmacokinetic properties, such as an increased apparent Caco-2
permeability (P.sub.app A-B) across Caco-2 cell monolayers,
compared to the compounds known from the prior art.
[0366] Further, preferred compounds of the present invention
according to formula (I) are characterized by improved
pharmacokinetic properties, such as a decreased efflux ratio
(efflux ratio=Pa.sub.pp B-A/Pa.sub.pp A-B) from the basal to apical
compartment across Caco-2 cell monolayers, compared to the
compounds known from the prior art.
[0367] In context of the present invention, the apparent Caco-2
permeability values from the basal to apical compartment (P.sub.app
A-B) or the efflux ratio (defined as the ratio ((P.sub.app
B-A)/(P.sub.app A-B)) are preferably determined according to Method
4. ("Caco-2 Permeation Assay") described in the Materials and
Method section below.
[0368] A further subject matter of the present invention is the use
of the compounds of general formula (I) according to the invention
for the treatment and/or prophylaxis of disorders, preferably of
disorders relating to or mediated by CDK9 activity, in particular
of hyper-proliferative disorders, virally induced infectious
diseases and/or of cardiovascular diseases, more preferably of
hyper-proliferative disorders.
[0369] The compounds of the present invention may be used to
inhibit the activity or expression of CDK9. Therefore, the
compounds of formula (I) are expected to be valuable as therapeutic
agents. Accordingly, in another embodiment, the present invention
provides a method of treating disorders relating to or mediated by
CDK9 activity in a patient in need of such treatment, comprising
administering to the patient an effective amount of a compound of
formula (I) as defined above. In certain embodiments, the disorders
relating to CDK9 activity are hyper-proliferative disorders,
virally induced infectious diseases and/or of cardiovascular
diseases, more preferably hyper-proliferative disorders,
particularly cancer.
[0370] The term "treating" or "treatment" as stated throughout this
document is used conventionally, e.g., the management or care of a
subject for the purpose of combating, alleviating, reducing,
relieving, improving the condition of a disease or disorder, such
as a carcinoma.
[0371] The term "subject" or "patient" includes organisms which are
capable of suffering from a cell proliferative disorder or a
disorder associated with reduced or insufficient programmed cell
death (apoptosis) or who could otherwise benefit from the
administration of a compound of the invention, such as human and
non-human animals. Preferred humans include human patients
suffering from or prone to suffering from a cell proliferative
disorder or associated state, as described herein. The term
"non-human animals" includes vertebrates, e.g., mammals, such as
non-human primates, sheep, cow, dog, cat and rodents, e.g., mice,
and non-mammals, such as chickens, amphibians, reptiles, etc.
[0372] The term "disorders relating to or mediated by CDK9" shall
include diseases associated with or implicating CDK9 activity, for
example the hyperactivity of CDK9, and conditions that accompany
with these diseases. Examples of "disorders relating to or mediated
by CDK9" include disorders resulting from increased CDK9 activity
due to mutations in genes regulating CDK9 activity auch as LARP7,
HEXIM1/2 or 7sk snRNA, or disorders resulting from increased CDK9
activity due to activation of the CDK9/cyclinT/RNApolymerase II
complex by viral proteins such as HIV-TAT or HTLV-TAX or disorders
resulting from increased CDK9 activity due to activation of
mitogenic signaling pathways.
[0373] The term "hyperactivity of CDK9" refers to increased
enzymatic activity of CDK9 as compared to normal non-diseased
cells, or it refers to increased CDK9 activity leading to unwanted
cell proliferation, or to reduced or insufficient programmed cell
death (apoptosis), or mutations leading to constitutive activation
of CDK9.
[0374] The term "hyper-proliferative disorder" includes disorders
involving the undesired or uncontrolled proliferation of a cell and
it includes disorders involving reduced or insufficient programmed
cell death (apoptosis). The compounds of the present invention can
be utilized to prevent, inhibit, block, reduce, decrease, control,
etc., cell proliferation and/or cell division, and/or produce
apoptosis. This method comprises administering to a subject in need
thereof, including a mammal, including a human, an amount of a
compound of this invention, or a pharmaceutically acceptable salt,
hydrate or solvate thereof which is effective to treat or prevent
the disorder.
[0375] Hyper-proliferative disorders in the context of this
invention include, but are not limited to, e.g., psoriasis, keloids
and other hyperplasias affecting the skin, endometriosis, skeletal
disorders, angiogenic or blood vessel proliferative disorders,
pulmonary hypertension, fibrotic disorders, mesangial cell
proliferative disorders, colonic polyps, polycystic kidney disease,
benign prostate hyperplasia (BPH), and solid tumors, such as
cancers of the breast, respiratory tract, brain, reproductive
organs, digestive tract, urinary tract, eye, liver, skin, head and
neck, thyroid, parathyroid, and their distant metastases. Those
disorders also include lymphomas, sarcomas and leukemias.
[0376] Examples of breast cancer include, but are not limited to
invasive ductal carcinoma, invasive lobular carcinoma, ductal
carcinoma in situ, and lobular carcinoma in situ, and canine or
feline mammary carcinoma.
[0377] Examples of cancers of the respiratory tract include, but
are not limited to small-cell and non-small-cell lung carcinoma, as
well as bronchial adenoma, pleuropulmonary blastoma, and
mesothelioma.
[0378] Examples of brain cancers include, but are not limited to
brain stem and hypophtalmic glioma, cerebellar and cerebral
astrocytoma, glioblastoma, medulloblastoma, ependymoma, as well as
neuroectodermal and pineal tumor.
[0379] Tumors of the male reproductive organs include, but are not
limited to prostate and testicular cancer.
[0380] Tumors of the female reproductive organs include, but are
not limited to endometrial, cervical, ovarian, vaginal and vulvar
cancer, as well as sarcoma of the uterus.
[0381] Tumors of the digestive tract include, but are not limited
to anal, colon, colorectal, esophageal, gallbladder, gastric,
pancreatic, rectal, small-intestine, and salivary gland cancers.
Anal gland adenocarcinomas, mast cell tumors.
[0382] Tumors of the urinary tract include, but are not limited to
bladder, penile, kidney, renal pelvis, ureter, urethral, and
hereditary and sporadic papillary renal cancers.
[0383] Eye cancers include, but are not limited to intraocular
melanoma and retinoblastoma.
[0384] Examples of liver cancers include, but are not limited to
hepatocellular carcinoma (liver cell carcinomas with or without
fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct
carcinoma), and mixed hepatocellular cholangiocarcinoma.
[0385] Skin cancers include, but are not limited to squamous cell
carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin
cancer, and non-melanoma skin cancer, mast cell tumors.
[0386] Head-and-neck cancers include, but are not limited to
laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer,
lip and oral cavity cancer, and squamous cell cancer. Oral
melanoma.
[0387] Lymphomas include, but are not limited to ADS-related
lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma,
Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central
nervous system.
[0388] Sarcomas include, but are not limited to sarcoma of the soft
tissue, osteosarcoma, malignant fibrous histiocytoma,
lymphosarcoma, and rhabdomyosarcoma. Malignant histiocytosis,
fibrosarcoma, hemangiosarcoma, hemangiopericytoma,
leiomyosarcoma.
[0389] Leukemias include, but are not limited to acute myeloid
leukemia, acute lymphoblastic leukemia, chronic lymphocytic
leukemia, chronic myelogenous leukemia, and hairy cell
leukemia.
[0390] Fibrotic proliferative disorders, i.e. the abnormal
formation of extracellular matrices, that may be treated with the
compounds and methods of the present invention include lung
fibrosis, atherosclerosis, restenosis, hepatic cirrhosis, and
mesangial cell proliferative disorders, including renal diseases
such as glomerulonephritis, diabetic nephropathy, malignant
nephrosclerosis, thrombotic microangiopathy syndromes, transplant
rejection, and glomerulopathies.
[0391] Other conditions in humans or other mammals that may be
treated by administering a compound of the present invention
include tumor growth, retinopathy, including diabetic retinopathy,
ischemic retinal-vein occlusion, retinopathy of prematurity and
age-related macular degeneration, rheumatoid arthritis, psoriasis,
and bullous disorders associated with subepidermal blister
formation, including bullous pemphigoid, erythema multiforme and
dermatitis herpetiformis.
[0392] The compounds of the present invention may also be used to
prevent and treat diseases of the airways and the lung, diseases of
the gastrointestinal tract as well as diseases of the bladder and
bile duct.
[0393] The disorders mentioned above have been well characterized
in humans, but also exist with a similar etiology in other animals,
including mammals, and can be treated by administering
pharmaceutical compositions of the present invention.
[0394] In a further aspect of the present invention, the compounds
according to the invention are used in a method for preventing
and/or treating infectious diseases, in particular virally induced
infectious diseases. The virally induced infectious diseases,
including opportunistic diseases, are caused by retroviruses,
hepadnaviruses, herpesviruses, flaviviridae, and/or adenoviruses.
In a further preferred embodiment of this method, the retroviruses
are selected from lentiviruses or oncoretroviruses, wherein the
lentivirus is selected from the group comprising: HIV-1, HIV-2,
FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV, preferably HIV-1 or HIV-2
and wherein the oncoretrovirus is selected from the group of:
HTLV-I, HTLV-II or BLV. In a further preferred embodiment of this
method, the hepadnavirus is selected from HBV, GSHV or WHV,
preferably HBV, the herpesivirus is selected from the group
comprising: HSV I, HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV
and the flaviviridae is selected from HCV, West nile or Yellow
Fever.
[0395] The compounds according to general formula (I) are also
useful for prophylaxis and/or treatment of cardiovascular diseases
such as cardiac hypertrophy, adult congenital heart disease,
aneurysm, stable angina, unstable angina, angina pectoris,
angioneurotic edema, aortic valve stenosis, aortic aneurysm,
arrhythmia, arrhythmogenic right ventricular dysplasia,
arteriosclerosis, arteriovenous malformations, atrial fibrillation,
Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaly,
congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive
cardiomyopathy, cardiovascular disease prevention, carotid
stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes,
Ebstein's Anomaly, Eisenmenger complex, cholesterol embolism,
bacterial endocarditis, fibromuscular dysplasia, congenital heart
defects, heart diseases, congestive heart failure, heart valve
diseases, heart attack, epidural hematoma, hematoma, subdural,
Hippel-Lindau disease, hyperemia, hypertension, pulmonary
hypertension, hypertrophic growth, left ventricular hypertrophy,
right ventricular hypertrophy, hypoplastic left heart syndrome,
hypotension, intermittent claudication, ischemic heart disease,
Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, long
QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneous
lymph node syndrome, myocardial infarction, myocardial ischemia,
myocarditis, pericarditis, peripheral vascular diseases, phlebitis,
polyarteritis nodosa, pulmonary atresia, Raynaud disease,
restenosis, Sneddon syndrome, stenosis, superior vena cava
syndrome, syndrome X, tachycardia, Takayasu's arteritis, hereditary
hemorrhagic telangiectasia, telangiectasis, temporal arteritis,
tetralogy of fallot, thromboangiitis obliterans, thrombosis,
thromboembolism, tricuspid atresia, varicose veins, vascular
diseases, vasculitis, vasospasm, ventricular fibrillation, Williams
syndrome, peripheral vascular disease, varicose veins and leg
ulcers, deep vein thrombosis, Wolff-Parkinson-White syndrome.
[0396] Preferred are cardiac hypertrophy, adult congenital heart
disease, aneurysms, angina, angina pectoris, arrhythmias,
cardiovascular disease prevention, cardiomyopathies, congestive
heart failure, myocardial infarction, pulmonary hypertension,
hypertrophic growth, restenosis, stenosis, thrombosis and
arteriosclerosis.
[0397] A further subject matter of the present invention is the use
of the compounds of general formula (I) according to the invention
for the treatment and/or prophylaxis of disorders, in particular of
the disorders mentioned above.
[0398] A further subject matter of the present invention are the
compounds according to the invention for use in a method for the
treatment and/or prophylaxis of the disorders mentioned above.
[0399] A preferred subject matter of the present invention are the
compounds according to the invention for the use in a method for
the treatment and/or prophylaxis of lung carcinomas, especially
non-small cell lung carcinomas, prostate carcinomas, especially
hormone-independent human prostate carcinomas, cervical carcinomas,
including multidrug-resistant human cervical carcinomas, colorectal
carcinomas, melanomas or ovarian carcinomas.
[0400] A further subject matter of the present invention is the use
of the compounds according to the invention in the manufacture of a
medicament for the treatment and/or prophylaxis of disorders, in
particular the disorders mentioned above.
[0401] A preferred subject matter of the present invention is the
use of the compounds according to the invention in the manufacture
of a medicament for the treatment and/or prophylaxis of lung
carcinomas, especially non-small cell lung carcinomas, prostate
carcinomas, especially hormone-independent human prostate
carcinomas, cervical carcinomas, including multidrug-resistant
human cervical carcinomas, colorectal carcinomas, melanomas or
ovarian carcinomas.
[0402] A further subject matter of the present invention is a
method for the treatment and/or prophylaxis of disorders, in
particular the disorders mentioned above, using an effective amount
of the compounds according to the invention.
[0403] A preferred subject matter of the present invention is a
method for the treatment and/or prophylaxis of lung carcinomas,
especially non-small cell lung carcinomas, prostate carcinomas,
especially hormone-independent human prostate carcinomas, cervical
carcinomas, including multidrug-resistant human cervical
carcinomas, colorectal carcinomas, melanomas or ovarian
carcinomas.
[0404] Another aspect of the present invention relates to
pharmaceutical combinations comprising a compound of general
formula (I) according to the invention in combination with at least
one or more further active ingredients.
[0405] As used herein the term "pharmaceutical combination" refers
to a combination of at least one compound of general formula (I)
according to the invention as active ingredient together with at
least one other active ingredient with or without further
ingredients, carrier, diluents and/or solvents.
[0406] Another aspect of the present invention relates to
pharmaceutical compositions comprising a compound of general
formula (I) according to the invention in combination with an
inert, nontoxic, pharmaceutically suitable adjuvant.
[0407] As used herein the term "pharmaceutical composition" refers
to a galenic formulation of at least one pharmaceutically active
agent together with at least one further ingredient, carrier,
diluent and/or solvent.
[0408] Another aspect of the present invention relates to the use
of the pharmaceutical combinations and/or the pharmaceutical
compositions according to the invention for the treatment and/or
prophylaxis of disorders, in particular of the disorders mentioned
above.
[0409] Compounds of formula (I) may be administered as the sole
pharmaceutical agent or in combination with one or more additional
therapeutic agents where the combination causes no unacceptable
adverse effects. This pharmaceutical combination includes
administration of a single pharmaceutical dosage formulation which
contains a compound of formula (I) and one or more additional
therapeutic agents, as well as administration of the compound of
formula (I) and each additional therapeutic agent in its own
separate pharmaceutical dosage formulation. For example, a compound
of formula (I) and a therapeutic agent may be administered to the
patient together in a single oral dosage composition such as a
tablet or capsule, or each agent may be administered in separate
dosage formulations.
[0410] Where separate dosage formulations are used, the compound of
formula (I) and one or more additional therapeutic agents may be
administered at essentially the same time (e.g., concurrently) or
at separately staggered times (e.g., sequentially).
[0411] In particular, the compounds of the present invention may be
used in fixed or separate combination with other anti-tumor agents
such as alkylating agents, anti-metabolites, plant-derived
anti-tumor agents, hormonal therapy agents, topoisomerase
inhibitors, camptothecin derivatives, kinase inhibitors, targeted
drugs, antibodies, interferons and/or biological response
modifiers, anti-angiogenic compounds, and other anti-tumor drugs.
In this regard, the following is a non-limiting list of examples of
secondary agents that may be used in combination with the compounds
of the present invention: [0412] Alkylating agents include, but are
not limited to, nitrogen mustard N-oxide, cyclophosphamide,
ifosfamide, thiotepa, ranimustine, nimustine, temozolomide,
altretamine, apaziquone, brostallicin, bendamustine, carmustine,
estramustine, fotemustine, glufosfamide, mafosfamide, bendamustin,
and mitolactol; platinum-coordinated alkylating compounds include,
but are not limited to, cisplatin, carboplatin, eptaplatin,
lobaplatin, nedaplatin, oxaliplatin, and satraplatin; [0413]
Anti-metabolites include, but are not limited to, methotrexate,
6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone or
in combination with leucovorin, tegafur, doxifluridine, carmofur,
cytarabine, cytarabine ocfosfate, enocitabine, gemcitabine,
fludarabin, 5-azacitidine, capecitabine, cladribine, clofarabine,
decitabine, eflomithine, ethynylcytidine, cytosine arabinoside,
hydroxyurea, melphalan, nelarabine, nolatrexed, ocfosfite, disodium
premetrexed, pentostatin, pelitrexol, raltitrexed, triapine,
trimetrexate, vidarabine, vincristine, and vinorelbine; [0414]
Hormonal therapy agents include, but are not limited to,
exemestane, Lupron, anastrozole, doxercalciferol, fadrozole,
formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors,
17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone
acetate, 5-alpha reductase inhibitors such as finasteride and
epristeride, anti-estrogens such as tamoxifen citrate and
fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,
letrozole, anti-androgens such as bicalutamide, flutamide,
mifepristone, nilutamide, Casodex, and anti-progesterones and
combinations thereof; [0415] Plant-derived anti-tumor substances
include, e.g., those selected from mitotic inhibitors, for example
epothilones such as sagopilone, ixabepilone and epothilone B,
vinblastine, vinflunine, docetaxel, and paclitaxel; [0416]
Cytotoxic topoisomerase inhibiting agents include, but are not
limited to, aclarubicin, doxorubicin, amonafide, belotecan,
camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin,
diflomotecan, irinotecan, topotecan, edotecarin, epimbicin,
etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,
pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and
combinations thereof; [0417] Immunologicals include interferons
such as interferon alpha, interferon alpha-2a, interferon alpha-2b,
interferon beta, interferon gamma-1a and interferon gamma-n1, and
other immune enhancing agents such as L19-IL2 and other IL2
derivatives, filgrastim, lentinan, sizofilan, TheraCys, ubenimex,
aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,
denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod,
lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,
sargramostim, tasonermin, tecleukin, thymalasin, tositumomab,
Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and
Provenge; Merial melanoma vaccine [0418] Biological response
modifiers are agents that modify defense mechanisms of living
organisms or biological responses such as survival, growth or
differentiation of tissue cells to direct them to have anti-tumor
activity; such agents include, e.g., krestin, lentinan, sizofiran,
picibanil, ProMune, and ubenimex; [0419] Anti-angiogenic compounds
include, but are not limited to, acitretin, aflibercept,
angiostatin, aplidine, asentar, axitinib, recentin, bevacizumab,
brivanib alaninat, cilengtide, combretastatin, DAST, endostatin,
fenretinide, halofuginone, pazopanib, ranibizumab, rebimastat,
removab, revlimid, sorafenib, vatalanib, squalamine, sunitinib,
telatinib, thalidomide, ukrain, and vitaxin; [0420] Antibodies
include, but are not limited to, trastuzumab, cetuximab,
bevacizumab, rituximab, ticilimumab, ipilimumab, lumiliximab,
catumaxomab, atacicept, oregovomab, and alemtuzumab; [0421] VEGF
inhibitors such as, e.g., sorafenib, DAST, bevacizumab, sunitinib,
recentin, axitinib, aflibercept, telatinib, brivanib alaninate,
vatalanib, pazopanib, and ranibizumab; Palladia [0422] EGFR (HER1)
inhibitors such as, e.g., cetuximab, panitumumab, vectibix,
gefitinib, erlotinib, and Zactima; [0423] HER2 inhibitors such as,
e.g., lapatinib, tratuzumab, and pertuzumab; [0424] mTOR inhibitors
such as, e.g., temsirolimus, sirolimus/Rapamycin, and everolimus;
[0425] c-Met inhibitors; [0426] PI3K and AKT inhibitors; [0427] CDK
inhibitors such as roscovitine and flavopiridol; [0428] Spindle
assembly checkpoints inhibitors and targeted anti-mitotic agents
such as PLK inhibitors, Aurora inhibitors (e.g. Hesperadin),
checkpoint kinase inhibitors, and KSP inhibitors; [0429] HDAC
inhibitors such as, e.g., panobinostat, vorinostat, MS275,
belinostat, and LBH589; [0430] HSP90 and HSP70 inhibitors; [0431]
Proteasome inhibitors such as bortezomib and carfilzomib; [0432]
Serine/threonine kinase inhibitors including MEK inhibitors (such
as e.g. RDEA 119) and Raf inhibitors such as sorafenib; [0433]
Farnesyl transferase inhibitors such as, e.g., tipifamib; [0434]
Tyrosine kinase inhibitors including, e.g., dasatinib, nilotibib,
DAST, bosutinib, sorafenib, bevacizumab, sunitinib, AZD2171,
axitinib, aflibercept, telatinib, imatinib mesylate, brivanib
alaninate, pazopanib, ranibizumab, vatalanib, cetuximab,
panitumumab, vectibix, gefitinib, erlotinib, lapatinib, tratuzumab,
pertuzumab, and c-Kit inhibitors; Palladia, masitinib [0435]
Vitamin D receptor agonists; [0436] Bcl-2 protein inhibitors such
as obatoclax, oblimersen sodium, and gossypol; [0437] Cluster of
differentiation 20 receptor antagonists such as, e.g., rituximab;
[0438] Ribonucleotide reductase inhibitors such as, e.g.,
gemcitabine; [0439] Tumor necrosis apoptosis inducing ligand
receptor 1 agonists such as, e.g., mapatumumab; [0440]
5-Hydroxytryptamine receptor antagonists such as, e.g., rEV598,
xaliprode, palonosetron hydrochloride, granisetron, Zindol, and
AB-1001; [0441] Integrin inhibitors including alpha5-beta1 integrin
inhibitors such as, e.g., E7820, JSM 6425, volociximab, and
endostatin; [0442] Androgen receptor antagonists including, e.g.,
nandrolone decanoate, fluoxymesterone, Android, Prost-aid,
andromustine, bicalutamide, flutamide, apo-cyproterone,
apo-flutamide, chlormadinone acetate, Androcur, Tabi, cyproterone
acetate, and nilutamide; [0443] Aromatase inhibitors such as, e.g.,
anastrozole, letrozole, testolactone, exemestane,
aminoglutethimide, and formestane; [0444] Matrix metalloproteinase
inhibitors; [0445] Other anti-cancer agents including, e.g.,
alitretinoin, ampligen, atrasentan bexarotene, bortezomib,
bosentan, calcitriol, exisulind, fotemustine, ibandronic acid,
miltefosine, mitoxantrone, I-asparaginase, procarbazine,
dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,
tazaroten, velcade, gallium nitrate, canfosfamide, darinaparsin,
and tretinoin.
[0446] The compounds of the present invention may also be employed
in cancer treatment in conjunction with radiation therapy and/or
surgical intervention.
[0447] Generally, the use of cytotoxic and/or cytostatic agents in
combination with a compound or composition of the present invention
will serve to: [0448] (1) yield better efficacy in reducing the
growth of a tumor or even eliminate the tumor as compared to
administration of either agent alone, [0449] (2) provide for the
administration of lesser amounts of the administered
chemotherapeutic agents, [0450] (3) provide for a chemotherapeutic
treatment that is well tolerated in the patient with fewer
deleterious pharmacological complications than observed with single
agent chemotherapies and certain other combined therapies, [0451]
(4) provide for treating a broader spectrum of different cancer
types in mammals, especially humans, [0452] (5) provide for a
higher response rate among treated patients, [0453] (6) provide for
a longer survival time among treated patients compared to standard
chemotherapy treatments, [0454] (7) provide a longer time for tumor
progression, and/or [0455] (8) yield efficacy and tolerability
results at least as good as those of the agents used alone,
compared to known instances where other cancer agent combinations
produce antagonistic effects.
[0456] Furthermore, the compounds of formula (I) may be utilized,
as such or in compositions, in research and diagnostics, or as
analytical reference standards, and the like, which are well known
in the art.
[0457] The compounds according to the invention can act
systemically and/or locally. For this purpose, they can be
administered in a suitable way, such as, for example, by the oral,
parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal,
dermal, transdermal, conjunctival or otic route, or as an implant
or stent.
[0458] For these administration routes, it is possible to
administer the compounds according to the invention in suitable
application forms.
[0459] Suitable for oral administration are administration forms
which work as described in the prior art and deliver the compounds
according to the invention rapidly and/or in modified form, which
comprise the compounds according to the invention in crystalline
and/or amorphous and/or dissolved form, such as, for example,
tablets (coated or uncoated, for example tablets provided with
enteric coatings or coatings whose dissolution is delayed or which
are insoluble and which control the release of the compound
according to the invention), tablets which rapidly decompose in the
oral cavity, or films/wafers, films/lyophilizates, capsules (for
example hard or soft gelatin capsules), sugar-coated tablets,
granules, pellets, powders, emulsions, suspensions, aerosols or
solutions.
[0460] Parenteral administration can take place with avoidance of
an absorption step (for example intravenously, intraarterially,
intracardially, intraspinally or intralumbally) or with inclusion
of absorption (for example intramuscularly, subcutaneously,
intracutaneously, percutaneously or intraperitoneally).
Administration forms suitable for parenteral administration are,
inter alia, preparations for injection and infusion in the form of
solutions, suspensions, emulsions, lyophilizates or sterile
powders.
[0461] Examples suitable for the other administration routes are
pharmaceutical forms for inhalation (inter alia powder inhalers,
nebulizers), nasal drops/solutions/sprays; tablets to be
administered lingually, sublingually or buccally, films/wafers or
capsules, suppositories, preparations for the eyes or ears, vaginal
capsules, aqueous suspensions (lotions, shaking mixtures),
lipophilic suspensions, ointments, creams, transdermal therapeutic
systems (such as plasters, for example), milk, pastes, foams,
dusting powders, implants or stents.
[0462] The compounds according to the invention can be converted
into the stated administration forms. This can take place in a
manner known per se by mixing with inert, nontoxic,
pharmaceutically suitable adjuvants. These adjuvants include, inter
alia, carriers (for example microcrystalline cellulose, lactose,
mannitol), solvents (for example liquid polyethylene glycols),
emulsifiers and dispersants or wetting agents (for example sodium
dodecyl sulphate, polyoxysorbitan oleate), binders (for example
polyvinylpyrrolidone), synthetic and natural polymers (for example
albumin), stabilizers (for example antioxidants, such as, for
example, ascorbic acid), colorants (for example inorganic pigments,
such as, for example, iron oxides) and flavour- and/or
odour-masking agents.
[0463] The present invention furthermore provides medicaments
comprising at least one compound according to the invention,
usually together with one or more inert, nontoxic, pharmaceutically
suitable adjuvants, and their use for the purposes mentioned
above.
[0464] When the compounds of the present invention are administered
as pharmaceuticals, to humans or animals, they can be given per se
or as a pharmaceutical composition containing, for example, 0.1% to
99.5% (more preferably 0.5% to 90%) of active ingredient in
combination with one or more inert, nontoxic, pharmaceutically
suitable adjuvants.
[0465] Regardless of the route of administration selected, the
compounds of the invention of general formula (I) and/or the
pharmaceutical composition of the present invention are formulated
into pharmaceutically acceptable dosage forms by conventional
methods known to those of skill in the art.
[0466] Actual dosage levels and time course of administration of
the active ingredients in the pharmaceutical compositions of the
invention may be varied so as to obtain an amount of the active
ingredient which is effective to achieve the desired therapeutic
response for a particular patient without being toxic to the
patient.
Materials and Methods:
[0467] The percentage data in the following tests and examples are
percentages by weight unless otherwise indicated; parts are parts
by weight. Solvent ratios, dilution ratios and concentration data
of liquid/liquid solutions are in each case based on volume.
[0468] Examples were tested in selected biological assays one or
more times. When tested more than once, data are reported as either
average values or as median values, wherein [0469] the average
value, also referred to as the arithmetic mean value, represents
the sum of the values obtained divided by the number of times
tested, and [0470] the median value represents the middle number of
the group of values when ranked in ascending or descending order.
If the number of values in the data set is odd, the median is the
middle value. If the number of values in the data set is even, the
median is the arithmetic mean of the two middle values.
[0471] Examples were synthesized one or more times. When
synthesized more than once, data from biological assays represent
average values or median values calculated utilizing data sets
obtained from testing of one or more synthetic batch.
[0472] The in vitro pharmacological properties of the compounds can
be determined according to the following assays and methods.
1a. CDK9/CycT1 Kinase Assay:
[0473] CDK9/CycT1-inhibitory activity of compounds of the present
invention was quantified employing the CDK9/CycT1 TR-FRET assay as
described in the following paragraphs:
[0474] Recombinant full-length His-tagged human CDK9 and CycT1,
expressed in insect cells and purified by Ni-NTA affinity
chromatography, were purchased from Invitrogen (Cat. No PV4131). As
substrate for the kinase reaction biotinylated peptide
biotin-Ttds-YISPLKSPYKISEG (C-terminus in amid form) was used which
can be purchased e.g. form the company JERINI Peptide Technologies
(Berlin, Germany).
[0475] For the assay 50 nl of a 100 fold concentrated solution of
the test compound in DMSO was pipetted into a black low volume 384
well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2
.mu.l of a solution of CDK9/CycT1 in aqueous assay buffer [50 mM
Tris/HCl pH 8.0, 10 mM MgCl.sub.2, 1.0 mM dithiothreitol, 0.1 mM
sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added
and the mixture was incubated for 15 min at 22.degree. C. to allow
pre-binding of the test compounds to the enzyme before the start of
the kinase reaction. Then the kinase reaction was started by the
addition of 3 .mu.l of a solution of adenosine-tri-phosphate (ATP,
16.7 .mu.M=>final conc. in the 5 .mu.l assay volume is 10 .mu.M)
and substrate (1.67 .mu.M=>final conc. in the 5 .mu.l assay
volume is 1 .mu.M) in assay buffer and the resulting mixture was
incubated for a reaction time of 25 min at 22.degree. C. The
concentration of CDK9/CycT1 was adjusted depending of the activity
of the enzyme lot and was chosen appropriate to have the assay in
the linear range, typical concentrations were in the range of 1
.mu.g/mL. The reaction was stopped by the addition of 5 .mu.l of a
solution of TR-FRET detection reagents (0.2 .mu.M
streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM
anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and
1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody
[Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution
(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES/NaOH
pH 7.0).
[0476] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the formation of complex between the phosphorylated
biotinylated peptide and the detection reagents. Subsequently the
amount of phosphorylated substrate was evaluated by measurement of
the resonance energy transfer from the Eu-chelate to the
streptavidine-XL. Therefore, the fluorescence emissions at 620 nm
and 665 nm after excitation at 350 nm was measured in a HTRF
reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany)
or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm
and at 622 nm was taken as the measure for the amount of
phosphorylated substrate. The data were normalised (enzyme reaction
without inhibitor=0% inhibition, all other assay components but no
enzyme=100% inhibition). Usually the test compounds were tested on
the same microtiterplate in 11 different concentrations in the
range of 20 .mu.M to 0.1 nM (20 .mu.M, 5.9 .mu.M, 1.7 .mu.M, 0.51
.mu.M, 0.15 .mu.M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1
nM, the dilution series prepared separately before the assay on the
level of the 100 fold concentrated solutions in DMSO by serial
1:3.4 dilutions) in duplicate values for each concentration and
IC.sub.50 values were calculated by a 4 parameter fit using an
inhouse software.
1b. CDK9/CycT1 High ATP Kinase Assay
[0477] CDK9/CycT1-inhibitory activity of compounds of the present
invention at a high ATP concentration after preincubation of enzyme
and test compounds was quantified employing the CDK9/CycT1 TR-FRET
assay as described in the following paragraphs.
[0478] Recombinant full-length His-tagged human CDK9 and CycT1,
expressed in insect cells and purified by Ni-NTA affinity
chromatography, were purchase from Invitrogen (Cat. No PV4131). As
substrate for the kinase reaction biotinylated peptide
biotin-Ttds-YISPLKSPYKISEG (C-terminus in amid form) was used which
can be purchased e.g. form the company JERINI peptide technologies
(Berlin, Germany).
[0479] For the assay 50 nl of a 100 fold concentrated solution of
the test compound in DMSO was pipetted into a black low volume 384
well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2
.mu.l of a solution of CDK9/CycT1 in aqueous assay buffer [50 mM
Tris/HCl pH 8.0, 10 mM MgCl.sub.2, 1.0 mM dithiothreitol, 0.1 mM
sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added
and the mixture was incubated for 15 min at 22.degree. C. to allow
pre-binding of the test compounds to the enzyme before the start of
the kinase reaction. Then the kinase reaction was started by the
addition of 3 .mu.l of a solution of adenosine-tri-phosphate (ATP,
3.3 mM=>final conc. in the 5 .mu.l assay volume is 2 mM) and
substrate (1.67 .mu.M=>final conc. in the 5 .mu.l assay volume
is 1 .mu.M) in assay buffer and the resulting mixture was incubated
for a reaction time of 25 min at 22.degree. C. The concentration of
CDK9/CycT1 was adjusted depending of the activity of the enzyme lot
and was chosen appropriate to have the assay in the linear range,
typical concentrations were in the range of 0.5 .mu.g/mL. The
reaction was stopped by the addition of 5 .mu.l of a solution of
TR-FRET detection reagents (0.2 .mu.M streptavidine-XL665 [Cisbio
Bioassays, Codolet, France] and 1 nM
anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and
1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody
[Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution
(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES/NaOH
pH 7.0).
[0480] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the formation of complex between the phosphorylated
biotinylated peptide and the detection reagents. Subsequently the
amount of phosphorylated substrate was evaluated by measurement of
the resonance energy transfer from the Eu-chelate to the
streptavidine-XL. Therefore, the fluorescence emissions at 620 nm
and 665 nm after excitation at 350 nm was measured in a HTRF
reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany)
or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm
and at 622 nm was taken as the measure for the amount of
phosphorylated substrate. The data were normalised (enzyme reaction
without inhibitor=0% inhibition, all other assay components but no
enzyme=100% inhibition). Usually the test compounds were tested on
the same microtiterplate in 11 different concentrations in the
range of 20 .mu.M to 0.1 nM (20 .mu.M, 5.9 .mu.M, 1.7 .mu.M, 0.51
.mu.M, 0.15 .mu.M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1
nM, the dilution series prepared separately before the assay on the
level of the 100 fold concentrated solutions in DMSO by serial
1:3.4 dilutions) in duplicate values for each concentration and
IC.sub.50 values were calculated by a 4 parameter fit using an
inhouse software.
2. CDK2/CycE Kinase Assay:
[0481] CDK2/CycE-inhibitory activity of compounds of the present
invention was quantified employing the CDK2/CycE TR-FRET assay as
described in the following paragraphs:
[0482] Recombinant fusion proteins of GST and human CDK2 and of GST
and human CycE, expressed in insect cells (Sf9) and purified by
Glutathion-Sepharose affinity chromatography, were purchased from
ProQinase GmbH (Freiburg, Germany). As substrate for the kinase
reaction biotinylated peptide biotin-Ttds-YISPLKSPYKISEG
(C-terminus in amid form) was used which can be purchased e.g. form
the company JERINI Peptide Technologies (Berlin, Germany).
[0483] For the assay 50 nl of a 100 fold concentrated solution of
the test compound in DMSO was pipetted into a black low volume 384
well microtiter plate (Greiner Bio-One, Frickenhausen, Germany), 2
.mu.l of a solution of CDK2/CycE in aqueous assay buffer [50 mM
Tris/HCl pH 8.0, 10 mM MgCl.sub.2, 1.0 mM dithiothreitol, 0.1 mM
sodium ortho-vanadate, 0.01% (v/v) Nonidet-P40 (Sigma)] were added
and the mixture was incubated for 15 min at 22.degree. C. to allow
pre-binding of the test compounds to the enzyme before the start of
the kinase reaction. Then the kinase reaction was started by the
addition of 3 .mu.l of a solution of adenosine-tri-phosphate (ATP,
16.7 .mu.M=>final conc. in the 5 .mu.l assay volume is 10 .mu.M)
and substrate (1.25 .mu.M=>final conc. in the 5 .mu.l assay
volume is 0.75 .mu.M) in assay buffer and the resulting mixture was
incubated for a reaction time of 25 min at 22.degree. C. The
concentration of CDK2/CycE was adjusted depending of the activity
of the enzyme lot and was chosen appropriate to have the assay in
the linear range, typical concentrations were in the range of 130
ng/mL. The reaction was stopped by the addition of 5 .mu.l of a
solution of TR-FRET detection reagents (0.2 .mu.M
streptavidine-XL665 [Cisbio Bioassays, Codolet, France] and 1 nM
anti-RB(pSer807/pSer811)-antibody from BD Pharmingen [#558389] and
1.2 nM LANCE EU-W1024 labeled anti-mouse IgG antibody
[Perkin-Elmer, product no. AD0077]) in an aqueous EDTA-solution
(100 mM EDTA, 0.2% (w/v) bovine serum albumin in 100 mM HEPES/NaOH
pH 7.0).
[0484] The resulting mixture was incubated 1 h at 22.degree. C. to
allow the formation of complex between the phosphorylated
biotinylated peptide and the detection reagents. Subsequently the
amount of phosphorylated substrate was evaluated by measurement of
the resonance energy transfer from the Eu-chelate to the
streptavidine-XL. Therefore, the fluorescence emissions at 620 nm
and 665 nm after excitation at 350 nm was measured in a TR-FRET
reader, e.g. a Rubystar (BMG Labtechnologies, Offenburg, Germany)
or a Viewlux (Perkin-Elmer). The ratio of the emissions at 665 nm
and at 622 nm was taken as the measure for the amount of
phosphorylated substrate. The data were normalised (enzyme reaction
without inhibitor=0% inhibition, all other assay components but no
enzyme=100% inhibition). Usually the test compounds were tested on
the same microtiterplate in 11 different concentrations in the
range of 20 .mu.M to 0.1 nM (20 .mu.M, 5.9 .mu.M, 1.7 .mu.M, 0.51
.mu.M, 0.15 .mu.M, 44 nM, 13 nM, 3.8 nM, 1.1 nM, 0.33 nM and 0.1
nM, the dilution series prepared separately before the assay on the
level of the 100 fold concentrated solutions in DMSO by serial
1:3.4 dilutions) in duplicate values for each concentration and
IC.sub.50 values were calculated by a 4 parameter fit using an
inhouse software.
3. Proliferation Assay:
[0485] Cultivated tumour cells (HeLa, human cervical tumour cells,
ATCC CCL-2; NCI-H460, human non-small cell lung carcinoma cells,
ATCC HTB-177; A2780, human ovarian carcinoma cells, ECACC
#93112519; DU 145, hormone-independent human prostate carcinoma
cells, ATCC HTB-81; HeLa-MaTu-ADR, multidrug-resistant human
cervical carcinoma cells, EPO-GmbH Berlin; Caco-2, human colorectal
carcinoma cells, ATCC HTB-37; B16F10, mouse melanoma cells, ATCC
CRL-6475) were plated at a density of 5,000 cells/well (DU145,
HeLa-MaTu-ADR), 3,000 cells/well (NCI-H460, HeLa), 2,500 cells/well
(A2780), 1,500 cells/well (Caco-2), or 1,000 cells/well (B16F10) in
a 96-well multititer plate in 200 .mu.L of their respective growth
medium supplemented 10% fetal calf serum. After 24 hours, the cells
of one plate (zero-point plate) were stained with crystal violet
(see below), while the medium of the other plates was replaced by
fresh culture medium (200 .mu.l), to which the test substances were
added in various concentrations (0 .mu.M, as well as in the range
of 0.001-10 .mu.M; the final concentration of the solvent dimethyl
sulfoxide was 0.5%). The cells were incubated for 4 days in the
presence of test substances. Cell proliferation was determined by
staining the cells with crystal violet: the cells were fixed by
adding 20 .mu.l/measuring point of an 11% glutaric aldehyde
solution for 15 minutes at room temperature. After three washing
cycles of the fixed cells with water, the plates were dried at room
temperature. The cells were stained by adding 100 .mu.l/measuring
point of a 0.1% crystal violet solution (pH 3.0). After three
washing cycles of the stained cells with water, the plates were
dried at room temperature. The dye was dissolved by adding 100
.mu.l/measuring point of a 10% acetic acid solution. The extinction
was determined by photometry at a wavelength of 595 nm. The change
of cell number, in percent, was calculated by normalization of the
measured values to the extinction values of the zero-point plate
(=0%) and the extinction of the untreated (0 .mu.m) cells (=100%).
The IC.sub.50 values (inhibitory concentration at 50% of maximal
effect) were determined by means of a 4 parameter fit.
4. Caco-2 Permeation Assay:
[0486] Caco-2 cells (purchased from DSMZ Braunschweig, Germany)
were seeded at a density of 4.5.times.10.sup.4 cells per well on 24
well insert plates, 0.4 .mu.m pore size, and grown for 15 days in
DMEM medium supplemented with 10% fetal bovine serum, 1% GlutaMAX
(100.times., GIBCO), 100 U/mL penicillin, 100 .mu.g/mL streptomycin
(GIBCO) and 1% non essential amino acids (100.times.). Cells were
maintained at 37.degree. C. in a humified 5% CO2 atmosphere. Medium
was changed every 2-3 day. Before running the permeation assay, the
culture medium was replaced by a FCS-free hepes-carbonate transport
buffer (pH 7.2). For assessment of monolayer integrity the
transepithelial electrical resistance (TEER) was measured. Test
compounds were predissolved in DMSO and added either to the apical
or basolateral compartment in final concentration of 2 .mu.M in
transport buffer. Before and after 2 h incubation at 37.degree. C.
samples were taken from both compartments. Analysis of compound
content was done after precipitation with methanol by LC/MS/MS
analysis. Permeability (Papp) was calculated in the apical to
basolateral (A.fwdarw.B) and basolateral to apical (B.fwdarw.A)
directions. The apparent permeability was calculated using
following equation:
Papp=(Vr/Po)(1/S)(P2/t)
Where Vr is the volume of medium in the receiver chamber, Po is the
measured peak area or height of the test drug in the donor chamber
at t=o, S the surface area of the monolayer, P2 is the measured
peak area of the test drug in the acceptor chamber after 2 h of
incubation, and t is the incubation time. The efflux ratio
basolateral (B) to apical (A) was calculated by dividing the Papp
B-A by the Papp A-B. In addition the compound recovery was
calculated. The following reference compounds were used for the
classification of the permeability class: Antipyrine, Pyrazosin,
Verapamil, Fluvastatin, Cimetidine, Ranitidine, Atenolol,
Sulfasalazine.
PREPARATIVE EXAMPLES
Syntheses of Compounds
[0487] The syntheses of the disubstituted 5-fluoro-pyrimidines
according to the present invention are preferably carried out
according to the general synthetic sequence, shown in scheme 1.
##STR00027##
[0488] In the first step 2,4-dichloro-5-fluoropyrimidine (1) is
reacted with a boronic acid derivative R.sup.2--B(OR).sub.2 of
formula (2) to give a compound of formula (3). The boronic acid
derivative (2) may be a boronic acid (R=--H) or an ester of the
boronic acid, e.g. its isopropyl ester (R=--CH(CH.sub.3).sub.2),
preferably an ester derived from pinacol in which the boronic acid
intermediate forms a 2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(R--R=--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--).
[0489] The coupling reaction is catalyzed by palladium catalysts,
e.g. by Pd(0) catalysts like
tetrakis(triphenylphosphine)palladium(0) [Pd(PPh.sub.3).sub.4],
tris(dibenzylideneacetone)di-palladium(0) [Pd.sub.2(dba).sub.3], or
by Pd(II) catalysts like
dichlorobis(triphenylphosphine)-palladium(II)
[Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and
triphenylphosphine or by
[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.
[0490] The reaction is preferably carried out in a mixture of a
solvent like 1,2-dimethoxyethane, dioxane, DMF, DME, THF, or
isopropanol with water and in the presence of a base like potassium
carbonate, sodium bicarbonate or potassium phosphate.
[0491] (review: D. G. Hall, Boronic Acids, 2005 WILEY-VCH Verlag
GmbH & Co. KGaA, Weinheim, ISBN 3-527-30991-8 and references
cited therein).
[0492] In the second step a compound of formula (3) is reacted with
a suitable aniline of formula (4) to give a compound of formula
(I).
[0493] This coupling reaction can be carried out in an alcohol like
1-butanol or in an inert solvent like DMF, THF, DME, dioxane or
mixtures of such solvents in the presence of an acid like hydrogen
chloride or 4-methylbenzenesulfonic acid. Preferably, the reaction
is carried out at a elevated temperatures, for example 140.degree.
C.
[0494] Alternatively, a compound of formula (I) is accessable by
Palladium-catalyzed C--N cross-coupling reactions of a compound of
formula (3) and an aniline of formula (4) (see schemes 2, 3 and 4
and for a review on C--N cross coupling reactions see for example:
a) L. Jiang, S. L. Buchwald in `Metal-Catalyzed Cross-Coupling
Reactions`, 2.sup.nd ed.: A. de Meijere, F. Diederich, Eds.:
Wiley-VCH: Weinheim, Germany, 2004).
[0495] Preferred is the use of suitable palladium precatalysts
based upon biarylmonphosphines that are easily activated and ensure
the formation of the active mono-ligated Pd(0) complex (see for
examples a) S. L. Buchwald et al, J. Am. Chem. Soc. 2008, 130,
6686; b) S. L. Buchwald et al, J. Am. Chem. Soc. 2008, 130, 13552).
The reactions are run in the presence of a weak base at elevated
temperatures (see for example: a) S. L: Buchwald et al, Tet. Lett.
2009, 50, 3672).
[0496] Most preferred is the herein described use of
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and potassium
phosphate in toluene and 1-methylpyrrolidin-2-one. The reactions
are preferably run under argon for 3 hours at 130.degree. C. in a
microwave oven or in an oil bath.
[0497] The syntheses of the disubstituted 5-fluoro-pyrimidines of
formula (13) according to the present invention can also be carried
out according to the general synthetic sequence, shown in scheme
2.
##STR00028##
[0498] In the first step 2,4-dichloro-5-fluoropyrimidine (1) is
reacted with a boronic acid derivative of formula (9) to give a
compound of formula (10). The boronic acid derivative (9) may be a
boronic acid (R=--H) or an ester of the boronic acid, e.g. its
isopropyl ester (R=--CH(CH.sub.3).sub.2), preferably an ester
derived from pinacol in which the boronic acid intermediate forms a
2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(R--R=--C(CH.sub.3).sub.2--C(CH.sub.3).sub.2--). The coupling
reaction is catalyzed by Pd catalysts, e.g. by Pd(0) catalysts like
tetrakis(triphenylphosphine)palladium(0) [Pd(PPh.sub.3).sub.4],
tris(dibenzylideneacetone)di-palladium(0) [Pd.sub.2(dba).sub.3], or
by Pd(II) catalysts like
dichlorobis(triphenylphosphine)-palladium(II)
[Pd(PPh.sub.3).sub.2Cl.sub.2], palladium(II) acetate and
triphenylphosphine or by
[1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
[Pd(dppf)Cl.sub.2]. The reaction is preferably carried out in a
mixture of a solvent like 1,2-dimethoxyethane, dioxane, DMF, DME,
THF, or isopropanol with water and in the presence of a base like
aqueous potassium carbonate, aqueous sodium bicarbonate or
potassium phosphate.
[0499] In the second step, a compound of formula (10) is reacted
with a suitable aniline of formula (4) to give the corresponding
cross-coupling product of formula (11). The compounds of formula
(11) can be prepared by Palladium-catalyzed C--N cross-coupling
reactions (for a review on C--N cross-coupling reactions see for
example: a) L. Jiang, S. L. Buchwald in `Metal-Catalyzed
Cross-Coupling Reactions`, 2.sup.nd ed.: A. de Meijere, F.
Diederich, Eds.: Wiley-VCH: Weinheim, Germany, 2004).
[0500] Preferred is the use of suitable palladium precatalysts
based upon biarylmonphosphines that are easily activated and ensure
the formation of the active mono-ligated Pd(0) complex (see for
examples a) S. L. Buchwald et al, J. Am. Chem. Soc. 2008, 130,
6686; b) S. L. Buchwald et al, J. Am. Chem. Soc. 2008, 130, 13552).
The reactions are run in the presence of a weak base at elevated
temperatures (see for example: a) S. L: Buchwald et al, Tet. Lett.
2009, 50, 3672). Most preferred is the herein described use of
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphen-
yl)[2-(2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether
adduct, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and
potassium phosphate in toluene and 1-methylpyrrolidin-2-one. The
reactions are preferably run under argon for 3 hours at 130.degree.
C. in a microwave oven or in an oil bath.
[0501] In the third step, the ortho-fluoro substituent in
4-position of the compound of formula (11) is replaced by a
suitable alkoxy group --OR.sup.5. The reaction is preferably
carried out by adding at least two equivalents of sodium hydride to
a solution of compound (II) and the respective alcohol (12) in DMF
at room temperature to give the desired sulfones of formula
(13).
Preparation of Compounds:
[0502] Abbreviations Used in the Description of the Chemistry and
in the Examples that Follow are:
[0503] CDCl.sub.3 (deuterated chloroform); cHex (cyclohexane); d
(doublet); DCM (dichloromethane); DIPEA (di-iso-propylethylamine);
DME (1,2-dimethoxyethane), DMF (dimethylformamide); DMSO (dimethyl
sulfoxide); eq (equivalent); ES (electrospray); EtOAc (ethyl
acetate); EtOH (ethanol); iPrOH (iso-propanol); mCPBA
(meta-chloroperoxybenzoic acid), MeCN (acetonitrile), MeOH
(methanol); MS (mass spectrometry); NBS (N-bromosuccinimide), NMR
(nuclear magnetic resonance); p (pentet); Pd(dppf)Cl.sub.2
([1,1'-bis(diphenylphosphino)ferrocene]dichloro palladium(II)
complex with dichloromethane); iPrOH (iso-propanol); q (quartet);
RT (room temperature); s (singlet); sat. aq. (saturated aqueous);
SiO.sub.2 (silica gel); TFA (trifluoroacetic acid); TFAA
(trifluoroacetic anhydride), THF (tetrahydrofuran); tr
(triplet).
[0504] The IUPAC names of the examples were generated using the
program `ACD/Name batch version 12.01` from ACD LABS.
EXAMPLE 1
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3
[(methylsulfonyl)methyl]phenyl}pyrimidin-2-amine
##STR00029##
[0505] Preparation of Intermediate 1.1
1-[(Methylsulfanyl)methyl]-3-nitrobenzene
##STR00030##
[0507] Sodium methanethiolate (13.5 g; 192 mmol) was added in two
portions to a stirred solution of 1-(chloromethyl)-3-nitrobenzene
(30.0 g; 175 mmol) in ethanol (360 mL) at -15.degree. C. The cold
bath was removed and the batch was stirred at room temperature for
3 hours. The batch was diluted with brine and extracted with ethyl
acetate (2.times.). The combined organic phases were washed with
water, dried (sodium sulfate), filtered and concentrated to give
the desired product (32.2 g) that was used without further
purification.
[0508] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.18 (m,
1H), 8.11 (m, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.75 (s, 2H), 2.01
(s, 3H).
Preparation of Intermediate 1.2
1-[(Methylsulfonyl)methyl]-3-nitrobenzene
##STR00031##
[0510] 3-Chlorobenzenecarboperoxoic acid (77%; 26.9 g; 120 mmol)
was added to a stirred solution of
1-[(methylsulfanyl)methyl]-3-nitrobenzene (10.0 g) in DCM (1305 mL)
at 0.degree. C. The batch was stirred at 0.degree. C. for 30
minutes and then 2.5 hours at room temperature. The batch was
diluted with water (300 mL) before sodium bicarbonate (11.0 g) was
added. The batch was extracted with DCM (2.times.). The combined
organic phases were filtered using a Whatman filter and
concentrated. The residue was purified by chromatography
(DCM/ethanol 95:5) and finally recrystallized from ethyl acetate to
give the desired product (6.2 g; 28.9 mmol).
[0511] .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) .delta.=8.28 (m,
1H), 8.22 (m, 1H), 7.83 (m, 1H), 7.69 (m, 1H), 4.68 (s, 2H), 2.93
(s, 3H).
Preparation of Intermediate 1.3
3-[(Methylsulfonyl)methyl]aniline
##STR00032##
[0513] Titanium(III)chloride solution (about 15%) in about 10%
hydrochloric acid (162 mL; Merck Schuchardt OHG) was added to a
stirred solution of 1-[(methylsulfonyl)methyl]-3-nitrobenzene (5.1
g; 23.8 mmol) in THF (250 mL) at room temperature and the batch was
stirred for 16 hours. By adding 1N sodium hydroxide solution the pH
value of the reaction mixture was raised to 10 before the batch was
extracted with ethyl acetate (2.times.). The combined organic
phases were washed with brine, filtered using a Whatman filter and
concentrated to give the desired product (4.5 g) that was used
without further purification.
[0514] .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) .delta.=6.97 (m,
1H), 6.51 (m, 3H), 5.13 (br, 2H), 4.23 (s, 2H), 2.83 (s, 3H).
Preparation of Intermediate 1.4
2-Chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine
##STR00033##
[0516] A batch with 2,4-dichloro-5-fluoropyrimidine (200 mg; 1.20
mmol; Aldrich Chemical Company Inc.),
(4-fluoro-2-methoxyphenyl)boronic acid (224 mg; 1.31 mmol; Aldrich
Chemical Company Inc.) and tetrakis(triphenylphosphin)palladium(0)
(138 mg; 0.12 mmol) in 1,2-dimethoxyethane (3.6 mL) and 2 M
solution of potassium carbonate (1.8 mL) was degassed using argon.
The batch was stirred under argon for 16 hours at 90.degree. C.
After cooling the batch was diluted with ethyl acetate and washed
with brine. The organic phase was filtered using a Whatman filter
and concentrated. The residue was purified by column chromatography
(hexane/ethyl acetate 1:1) to give the desired product (106 mg;
0.41 mmol).
[0517] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.47 (m,
1H), 7.51 (m, 1H), 6.82 (m, 1H), 6.73 (m, 1H), 3.85 (s, 3H).
Preparation of End Product
[0518] 4N solution of hydrogen chloride in dioxane (41 .mu.L; 0.16
mmol) was added to a stirred solution of
2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (42 mg;
0.16 mmol) and 3-[(methylsulfonyl)methyl]aniline (30 mg; 0.16 mmol)
in 1-butanol (0.8 mL). The batch was stirred at 100.degree. C. for
27 hours before the temperature was raised to 140.degree. C. The
batch was stirred at this temperature for additional 22 hours.
After cooling the batch was concentrated and the residue was
purified by preparative HPLC to give the desired product (15 mg;
0.04 mmol).
TABLE-US-00001 System: Waters Autopurificationsystem: Pump 254,
Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1%
HCOOH B = MeCN Gradient: 0-1 min 50% B, 1-8 min 50-90% B Flow: 50
mL/min Temperatuer: RT Detection: DAD scan range 210-400 nm MS
ESI+, ESI-, scan range 160-1000 m/z ELSD Retention: 6.2-6.6 min
[0519] .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) .delta.=9.83 (m,
1H), 8.51 (m, 1H), 7.69 (m, 2H), 7.50 (m, 1H), 7.25 (m, 1H), 7.08
(m, 1H), 6.91 (m, 2H), 4.37 (s, 2H), 3.80 (s, 3H), 2.86 (s,
3H).
Alternative Procedure for the Preparation of End Product
[0520] A batch with 3-[(methylsulfonyl)methyl]aniline (108 mg; 0.58
mmol), 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine
(150 mg; 0.58 mmol), tris(dibenzylideneacetone)dipalladium(0) (96
mg; 0.11 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (88
mg; 0.15 mmol) and cesium carbonate (800 mg; 2.46 mmol) in dioxane
(1.0 mL) was degassed using argon. The batch was stirred under
argon for 150 minutes at 100.degree. C. After cooling, the batch
was filtered and the filter was rinsed with DCM and ethyl acetate.
The filtrate was concentrated in vacuo and the residue was purified
by preparative HPLC to give the desired product (49 mg; 0.12
mmol).
EXAMPLE 2
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(methylsulfonyl)methyl]phe-
nyl}pyrimidin-2-amine
##STR00034##
[0521] Preparation of Intermediate 2.1
4-[2-(Benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine
##STR00035##
[0523] Intermediate 2.1. was prepared under similar conditions as
described in the preparation of Intermediate 1.4. using
2,4-dichloro-5-fluoropyrimidine (Aldrich Chemical Company Inc.) and
[2-(benzyloxy)-4-fluorophenyl]boronic acid (ABCR GmbH & CO.
KG). The batch was purified by column chromatography (hexane/ethyl
acetate 1:1).
[0524] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.44 (m,
1H), 7.54 (m, 1H), 7.35 (m, 5H), 6.83 (m, 1H), 6.79 (m, 1H), 5.11
(s, 2H).
Preparation of End Product
[0525] 4N solution of hydrogen chloride in dioxane (0.11 mL; 0.45
mmol) was added to a stirred solution of
4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine (150
mg; 0.45 mmol) and 3-[(methylsulfonyl)methyl]aniline (84 mg; 0.45
mmol) in 1-butanol (1.0 mL). The batch was stirred at 140.degree.
C. for 20 hours. Additional 3-[(methylsulfonyl)methyl]aniline (84
mg; 0.45 mmol) was added and the batch was stirred at 140.degree.
C. for further 60 hours. After cooling the batch was diluted with
ethyl acetate and sodium bicarbonate solution. The organic phase
was filtered using a Whatman filter and concentrated. The residue
was purified by preparative HPLC to give the desired product (64
mg; 0.13 mmol).
TABLE-US-00002 System: Waters Autopurificationsystem: Pump 2545,
Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1%
HCOOH B = MeCN Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min
99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max.
2.5 mL DMSO or DMF Injektion: 1 .times. 2.5 mL Detection: DAD scan
range 210-400 nm MS ESI+, ESI-, scan range 160-1000 m/z
[0526] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.29 (m,
1H), 7.81 (m, 1H), 7.53 (m, 2H), 7.34 (m, 6H), 7.20 (br, 1H), 7.05
(m, 1H), 6.81 (m, 2H), 5.13 (s, 2H), 4.22 (s, 2H), 2.74 (s,
3H).
EXAMPLE 3
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-(3-{[(2-methoxyethyl)sulfonyl]-
methyl}phenyl)pyrimidin-2-amine
##STR00036##
[0528] 4N solution of hydrogen chloride in dioxane (0.11 mL; 0.45
mmol) was added to a stirred solution of
4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine (150
mg; 0.45 mmol) and 3-{[(2-methoxyethyl)sulfonyl]methyl}aniline (155
mg; 0.68 mmol; UkrOrgSynthesis Ltd.) in 1-butanol (1.0 mL). The
batch was stirred at 140.degree. C. for 60 hours. After cooling the
batch was diluted with ethyl acetate and sodium bicarbonate
solution. The organic phase was filtered using a Whatman filter and
concentrated. The residue was purified by preparative HPLC to give
the desired product (19 mg; 0.04 mmol).
TABLE-US-00003 System: Waters Autopurificationsystem: Pump 2545,
Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1%
HCOOH B = MeCN Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min
99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max.
2.5 mL DMSO or DMF Injektion: 1 .times. 2.5 mL Detection: DAD scan
range 210-400 nm MS ESI+, ESI-, scan range 160-1000 m/z
[0529] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.29 (m,
1H), 7.72 (m, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 7.34 (m, 6H), 7.18
(br, 1H), 7.09 (m, 1H), 6.80 (m, 2H), 5.12 (s, 2H), 4.31 (s, 2H),
3.79 (tr, 2H), 3.40 (s, 3H), 3.08 (tr, 2H).
EXAMPLE 4
4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(tert-butylsulfonyl)methyl]phenyl}--
5-fluoropyrimidin-2-amine
##STR00037##
[0531] Example 4 was prepared under similar conditions as described
in the preparation of Example 3 using
4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and
3-[(tert-butylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The
batch was purified by preparative HPLC.
TABLE-US-00004 System: Waters Autopurificationsystem: Pump 2545,
Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1%
HCOOH B = MeCN Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min
99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max.
2.5 mL DMSO or DMF Injektion: 1 .times. 2.5 mL Detection: DAD scan
range 210-400 nm MS ESI+, ESI-, scan range 160-1000 m/z
[0532] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.28 (m,
1H), 7.77 (m, 1H), 7.63 (m, 1H), 7.56 (m, 1H), 7.34 (m, 6H), 7.18
(br, 1H), 7.08 (m, 1H), 6.80 (m, 2H), 5.12 (s, 2H), 4.19 (s, 2H),
1.43 (s, 9H).
EXAMPLE 5
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-[(propan-2-ylsulfonyl)methy-
l]phenyl}pyrimidin-2-amine
##STR00038##
[0534] Example 5 was prepared under similar conditions as described
in the preparation of Example 3 using
4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and
3-[(propan-2-ylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The
batch was purified by preparative HPLC.
TABLE-US-00005 System: Waters Autopurificationsystem: Pump 2545,
Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1%
HCOOH B = MeCN Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min
99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max.
2.5 mL DMSO or DMF Injektion: 1 .times. 2.5 mL Detection: DAD scan
range 210-400 nm MS ESI+, ESI-, scan range 160-1000 m/z
[0535] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.29 (m,
1H), 7.81 (m, 1H), 7.55 (m, 2H), 7.34 (m, 6H), 7.22 (br, 1H), 7.06
(m, 1H), 6.81 (m, 2H), 5.12 (s, 2H), 4.21 (s, 2H), 3.03 (m, 1H),
1.34 (d, 6H).
EXAMPLE 6
4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(cyclohexylsulfonyl)methyl]phenyl}--
5-fluoropyrimidin-2-amine
##STR00039##
[0537] Example 6 was prepared under similar conditions as described
in the preparation of Example 3 using
4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and
3-[(cyclohexylsulfonyl)methyl]aniline (UkrOrgSynthesis Ltd.). The
batch was purified by preparative HPLC.
TABLE-US-00006 System: Waters Autopurificationsystem: Pump 2545,
Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1%
HCOOH B = MeCN Gradient: 0-1 min 1% B, 1-8 min 1-99% B, 8-10 min
99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250 mg/max.
2.5 mL DMSO or DMF Injektion: 1 .times. 2.5 mL Detection: DAD scan
range 210-400 nm MS ESI+, ESI-, scan range 160-1000 m/z
[0538] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.29 (m,
1H), 7.81 (m, 1H), 7.56 (m, 2H), 7.32 (m, 6H), 7.21 (br, 1H), 7.03
(m, 1H), 6.82 (m, 2H), 5.12 (s, 2H), 4.18 (s, 2H), 2.77 (m, 1H),
2.12 (m, 2H), 1.86 (m, 2H), 1.63 (m, 2H), 1.21 (m, 4H).
EXAMPLE 7
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-[(propan-2-ylsulfonyl)methyl]ph-
enyl}pyrimidin-2-amine
##STR00040##
[0539] Preparation of Intermediate 7.1
1-Nitro-3-[(propan-2-ylsulfanyl)methyl]benzene
##STR00041##
[0541] A solution of sodium methoxide (15.5 mL, 25 wt % in
methanol) was diluted with methanol (85 mL) and treated with
2-propanethiol (6.3 mL) at room temperature for 60 minutes, cooled
to -15.degree. C., treated with 3-nitrobenzylchloride (10 g) in 3
portions, kept for 2 hours at -15.degree. C., then the temperature
was increased to room temperature. The reaction mixture was
concentrated in vacuo, treated with diethyl ether (300 mL), washed
with water (2.times.100 mL) and brine (100 mL), dried with sodium
sulfate and evaporated to dryness. The title compound (12.3 g) was
thus obtained and used without further purification.
Preparation of Intermediate 7.2
1-Nitro-3-[(propan-2-ylsulfonyl)methyl]benzene
##STR00042##
[0543] A solution of 1-nitro-3-[(propan-2-ylsulfanyl)methyl]benzene
(4.0 g) in DCM (160 mL) was treated at 0.degree. C. with portions
of m-chloroperbenzoic acid (9.3 g, 77%). The mixture was stirred at
0.degree. C. for further 30 minutes and then 18 hours at room
temperature. The reaction mixture was diluted with DCM before
sodium hydrogen sulfite and sodium bicarbonate solution was added
and extracted with DCM (2.times.). The combined organic phases were
washed and concentrated. The residue was purified by chromatography
(hexane/ethyl acetate 12%-100%) to give the title compound (4.5
g).
Preparation of Intermediate 7.3
N-{3-[(Propan-2-ylsulfonyl)methyl]phenyl}acetamide
##STR00043##
[0545] A suspension of crude
1-nitro-3-[(propan-2-ylsulfonyl)methyl]benzene (5.0 g) in acetic
acid (58 mL) was treated with iron powder (4.7 g), heated for 22
hours at 110.degree. C. bath temperature and cooled to room
temperature. Then water (250 mL) and DCM (250 mL) were added,
stirred, filtered, dried with sodium sulfate, filtered and
concentrated. An analytical sample (200 mg) of the crude title
compound (5.6 g) was recrystallized from diethyl ether/ethanol (121
mg). Lit.: [Grohmann and Hathaway, Molbank 2006, M502].
[0546] .sup.1H-NMR (600 MHz, CDCl.sub.3): .delta.=7.61 (s, 1H),
7.50 (d, 1H), 7.37 (br. s., 1H), 7.32 (t, 1H), 7.14 (d, 1H), 4.20
(s, 2H), 3.05 (spt, 1H), 2.16 (s, 3H), 1.39 (d, 6H).
Preparation of Intermediate 7.4
3-[(Propan-2-ylsulfonyl)methyl]anilinium chloride
##STR00044##
[0548] A solution of
N-{3-[(propan-2-ylsulfonyl)methyl]phenyl}acetamide (5.4 g) in
ethanol (29.6 mL) was treated with concentrated hydrochloric acid
(35.5 mL) and refluxed for 24 hours. The reaction mixture was
condensed to dryness. The title compound (3.5 g) was obtained by
crystallization from ethanol/ethyl acetate.
[0549] .sup.1H-NMR (400 MHz, d.sub.6-DMSO): .delta.=9.95 (br. s.,
2H), 7.47 (m, 1H), 7.34 (m, 3H), 4.52 (s, 2H), 3.22 (spt, 1H), 1.29
(d, 6H).
Preparation of End Product
[0550] A batch with
2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (150 mg;
0.58 mmol) and 3-[(propan-2-ylsulfonyl)methyl]anilinium chloride
(146 mg; 0.58 mmol) in 1-butanol (2.9 mL) was stirred at
120.degree. C. for 48 hours. The temperature was raised to
140.degree. C. and the batch was stirred for additional 24 hours.
After cooling the batch was concentrated in vacuo. Sodium
bicarbonate solution and ethyl acetate were added. The organic
phase was washed with sodium chloride solution, dried with sodium
sulfate, filtered and concentrated. The residue was purified by
chromatography (hexane/ethyl acetate 7%-60%) to give the desired
product (214 mg; 0.49 mmol).
[0551] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=8.30 (m, 1H), 7.81
(m, 1H), 7.58 (m, 1H), 7.50 (m, 1H), 7.33 (m, 1H), 7.20 (br, 1H),
7.07 (m, 1H), 6.81 (m, 1H), 6.75 (m, 1H), 4.21 (s, 2H), 3.86 (s,
3H), 3.04 (m, 1H), 1.34 (d, 6H).
EXAMPLE 8
2-[(3-{[5-Fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-yl]amino}benzyl)s-
ulfonyl]ethanol
##STR00045##
[0553] Example 8. was prepared under similar conditions as
described in the preparation of Example 1 using
2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and
2-[(3-aminobenzyl)sulfonyl]ethanol. The batch was purified by
chromatography (hexane/ethyl acetate 7%-100%).
[0554] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=8.30 (m, 1H), 7.83
(m, 1H), 7.56 (m, 1H), 7.49 (m, 1H), 7.35 (m, 1H), 7.09 (m, 1H),
6.82 (m, 1H), 6.76 (m, 1H), 4.33 (s, 2H), 4.04 (m, 2H), 3.86 (s,
3H), 3.09 (m, 2H), 2.49 (br, 1H).
EXAMPLE 9
4-(3,4-Dihydro-2H-chromen-8-yl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phen-
yl}pyrimidin-2-amine
##STR00046##
[0555] Preparation of Intermediate 9.1
2-Chloro-4-(3,4-dihydro-2H-chromen-8-yl)-5-fluoropyrimidine
##STR00047##
[0557] A batch with 2,4-dichloro-5-fluoropyrimidine (565 mg; 3.28
mmol; Aldrich Chemical Company Inc.),
3,4-dihydro-2H-chromen-8-ylboronic acid (643 mg; 3.61 mmol; Parkway
Scientific LLC) and bis(triphenylphosphine)palladium(II)chloride
(230 mg; 0.33 mmol) in 1,2-dimethoxyethane (5.4 mL) and 2 M
solution of potassium carbonate (4.9 mL) was degassed using argon.
The batch was stirred under argon for 16 hours at 90.degree. C.
After cooling the batch was diluted with ethyl acetate and washed
with brine. The organic phase dried (sodium sulfate), filtered and
concentrated. The residue was purified by chromatography
(hexane/ethyl acetate 2%-20%) to give the desired product (701 mg;
2.57 mmol).
[0558] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.44 (m,
1H), 7.31 (m, 1H), 7.21 (m, 1H), 6.97 (m, 1H), 4.20 (tr, 2H), 2.86
(tr, 2H), 2.04 (m, 2H).
Preparation of End Product
[0559] A batch with 3-[(methylsulfonyl)methyl]aniline (40.0 mg;
0.212 mmol),
2-chloro-4-(3,4-dihydro-2H-chromen-8-yl)-5-fluoropyrimidine (72.8
mg; 0.275 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct
(13.1 mg; 0.016 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (7.6 mg;
0.016 mmol) and potassium phosphate (224.6 mg; 1.058 mmol) in
toluene (2.7 mL) and 1-methylpyrrolidin-2-one (0.36 mL) was
degassed using argon. The batch was stirred under argon for 3 hours
at 130.degree. C. in a microwave oven.
[0560] After cooling, UPLC-MS analysis of the reaction mixture
indicated the desired product.
[0561] The reaction was repeated with a second batch using
3-[(methylsulfonyl)methyl]aniline (120.0 mg; 0.635 mmol),
2-chloro-4-(3,4-dihydro-2H-chromen-8-yl)-5-fluoropyrimidine (218.4
mg; 0.825 mmol),
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl]palladium(II) methyl-tert-butylether adduct
(39.3 mg; 0.048 mmol),
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (22.7 mg;
0.048 mmol) and potassium phosphate (673.7 mg; 3.174 mmol) in
toluene (8.1 mL) and 1-methylpyrrolidin-2-one (1.0 mL).
[0562] Both batches were combined, diluted with water and extracted
with ethyl acetate (3.times.). The combined organic phases were
dried (sodium sulfate), filtered and concentrated. The residue was
purified by chromatography (hexane/ethyl acetate 12%-100%) to give
the desired product (191.0 mg; 0.46 mmol).
[0563] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 300K) .delta.=9.78 (m,
1H), 8.48 (m, 1H), 7.73 (br, 1H), 7.71 (m, 1H), 7.24 (m, 3H), 6.93
(m, 2H), 4.37 (s, 2H), 4.13 (tr, 2H), 2.86 (s, 3H), 2.80 (tr, 2H),
1.91 (m, 2H).
EXAMPLE 10
N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-4-(3,4-dihydro-2H-chromen-8-yl)--
5-fluoropyrimidin-2-amine
##STR00048##
[0564] Preparation of Intermediate 10.1
1-[(Cyclopropylsulfonyl)methyl]-3-nitrobenzene
##STR00049##
[0566] Sodium cyclopropanesulfinate (1.04 g; 8.1 mmol) was added to
a solution of 1-(bromomethyl)-3-nitrobenzene (1.17 g; 5.4 mmol) in
acetonitrile (50 mL) at room temperature. The batch was stirred at
90.degree. C. for 4 hours. After cooling, the batch was diluted
with water and extracted with DCM (2.times.). The combined organic
phases were filtered using a Whatman filter and concentrated to
give the desired product (1.26 g; 5.2 mmol) that was used without
further purifications.
[0567] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.28 (m,
2H), 7.81 (m, 1H), 7.61 (m, 1H), 4.37 (s, 2H), 2.29 (m, 1H), 1.20
(m, 2H), 1.03 (m, 2H).
Preparation of Intermediate 10.2
3-[(Cyclopropylsulfonyl)methyl]aniline
##STR00050##
[0569] Intermediate 10.2. was prepared under similar conditions as
described in the preparation of Intermediate 1.3. using
1-[(cyclopropylsulfonyl)methyl]-3-nitrobenzene and
titanium(III)chloride solution (about 15%) in about 10%
hydrochloric acid (Merck Schuchardt OHG). The batch was purified by
chromatography (DCM/EtOH 95:5).
[0570] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=7.15 (m,
1H), 6.77 (m, 2H), 6.60 (m, 1H), 4.16 (s, 2H), 3.65 (br, 2H), 2.23
(m, 1H), 1.15 (m, 2H), 0.93 (m, 2H),
Preparation of End Product
[0571] Example 10 was prepared under similar conditions as
described in the preparation of Example 9 using
2-chloro-4-(3,4-dihydro-2H-chromen-8-yl)-5-fluoropyrimidine,
3-[(cyclopropylsulfonyl)methyl]aniline,
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and potassium
phosphate. The batch was purified by preparative HPLC.
TABLE-US-00007 System: Waters Autopurificationsystem: Pump 2545,
Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1%
HCOOH B = Acetonitrile Gradient: 0-1 min 1% B, 1-8 min 1-99% B,
8-10 min 99% B Flow: 50 mL/min Temperature: RT Solution: Max. 250
mg/max. 2.5 mL DMSO o. DMF Injektion: 1 .times. 2.5 mL Detection:
DAD scan range 210-400 nm MS ESI+, ESI-, scan range 160-1000
m/z
[0572] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.28 (m,
1H), 7.85 (m, 1H), 7.56 (m, 1H), 7.30 (m, 3H), 7.19 (m, 1H), 7.07
(m, 1H), 6.96 (m, 1H), 4.24 (s, 2H), 4.22 (tr, 2H), 2.88 (tr, 2H),
2.21 (m, 1H), 2.05 (m, 2H), 1.11 (m, 2H), 0.87 (m, 2H).
EXAMPLE 11
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3-fluoro-5-[(methylsulfonyl)m-
ethyl]phenyl}pyrimidin-2-amine
##STR00051##
[0573] Preparation of Intermediate 11.1
1-Fluoro-3-[(methylsulfanyl)methyl]-5-nitrobenzene
##STR00052##
[0575] Sodium methanethiolate (1.22 g; 17.4 mmol) was added in
three portions to a stirred solution of
1-(chloromethyl)-3-fluoro-5-nitrobenzene (3.00 g; 15.8 mmol, HE
Chemical) in ethanol (33 mL) at 0.degree. C. The ice bath was
removed and the batch was stirred at room temperature for 18 hours.
Further sodium methanethiolate (0.33 g; 4.7 mmol) was added and the
batch was stirred for 5 additional hours at room temperature. The
batch was diluted with brine and extracted with ethyl acetate
(2.times.). The combined organic phases were washed with water,
dried (sodium sulfate), filtered and concentrated to give the
desired product (3.4 g) that was used without further
purification.
[0576] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.00 (m,
1H), 7.81 (m, 1H), 7.42 (m, 1H), 3.74 (s, 2H), 2.02 (s, 3H).
Preparation of Intermediate 11.2
1-Fluoro-3-[(methylsulfonyl)methyl]-5-nitrobenzene
##STR00053##
[0578] 3-Chlorobenzenecarboperoxoic acid (77%; 3.68 g; 16.4 mmol)
was added to a stirred solution of
1-fluoro-3-[(methylsulfanyl)methyl]-5-nitrobenzene (1.50 g) in DCM
(178 mL) at 0.degree. C. The batch was stirred at 0.degree. C. for
30 minutes and then 2.5 hours at room temperature. The batch was
diluted with water (450 mL) before sodium bicarbonate (1.50 g) was
added. The batch was extracted with DCM (2.times.). The combined
organic phases were filtered using a Whatman filter and
concentrated to give the crude product (3.33 g) that was used
without further purification.
Preparation of Intermediate 11.3
3-Fluoro-5-[(methylsulfonyl)methyl]aniline
##STR00054##
[0580] Titanium(III)chloride solution (about 15%) in about 10%
hydrochloric acid (29 mL, Merck Schuchardt OHG) was added to a
stirred solution of crude
1-fluoro-3-[(methylsulfonyl)methyl]-5-nitrobenzene (1.00 g) in THF
(45 mL) at room temperature and the batch was stirred for 16 hours.
The batch was cooled with an ice bath while 1N sodium hydroxide
solution was added to raise the pH value of the reaction mixture to
8-9. It was stirred for 30 minutes at this temperature before the
batch was extracted with ethyl acetate (2.times.). The combined
organic phases were washed with brine, filtered using a Whatman
filter and concentrated. The residue was purified by column
chromatography (hexane/ethyl acetate 1:1 to ethyl acetate) to give
the desired product (262 mg; 1.29 mmol).
[0581] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=6.48 (m,
2H), 6.39 (m, 1H), 4.11 (s, 2H), 3.88 (br, 2H), 2.79 (s, 3H).
Preparation of End Product
[0582] Example 11 was prepared under similar conditions as
described in the preparation of Example 1 using
4-[2-(benzyloxy)-4-fluorophenyl]-2-chloro-5-fluoropyrimidine and
3-fluoro-5-[(methylsulfonyl)methyl]aniline. The batch was purified
by preparative HPLC.
TABLE-US-00008 System: Waters Autopurificationsystem: Pump 254,
Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001 Column:
XBrigde C18 5 .mu.m 100 .times. 30 mm Solvent: A = H.sub.2O + 0.1%
HCOOH B = MeCN Gradient: 0-1 min 50% B, 1-8 min 50-90% B, 8-8.1 min
90-100% B, 8.1-10 min 100% B Flow: 50 mL/min Temperature: RT
Detection: DAD scan range 210-400 nm MS ESI+, ESI-, scan range
160-1000 m/z ELSD Retention: 5.0-5.3 min
[0583] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.32 (m,
1H), 7.67 (m, 1H), 7.51 (m, 1H), 7.32 (m, 7H), 6.80 (m, 3H), 5.13
(s, 2H), 4.19 (s, 2H), 2.78 (s, 3H).
EXAMPLE 12
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-fluoro-5-[(methylsulfonyl)methy-
l]phenyl}pyrimidin-2-amine
##STR00055##
[0585] Example 12 was prepared under similar conditions as
described in the preparation of Example 1 using
2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and
3-fluoro-5-[(methylsulfonyl)methyl]aniline. The batch was purified
by preparative HPLC.
TABLE-US-00009 System: Column: Waters Autopurificationsystem: Pump
254, Sample Manager 2767, CFO, DAD 2996, ELSD 2424, SQD 3001
Solvent: XBrigde C18 5 .mu.m 100 .times. 30 mm A = H.sub.2O + 0.2%
NH.sub.3 Gradient: B = MeOH Flow: 0-1 min 50% B, 1-8 min 50-90% B,
8-8.1 min 90-100% B, 8.1-10 min 100% B Temperature: 50 mL/min
Detection: DAD scan range 210-400 nm MS ESI+, ESI-, scan range
160-1000 m/z ELSD Retention: 5.5-6.2 min
[0586] .sup.1H NMR (400 MHz, CDCl.sub.3, 300K) .delta.=8.33 (m,
1H), 7.72 (m, 1H), 7.48 (m, 1H), 7.31 (m, 2H), 6.78 (m, 3H), 4.20
(s, 2H), 3.87 (s, 3H), 2.80 (s, 3H).
EXAMPLE 13
4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-5-fluoro-N-{3-[(methylsulfonyl)methyl-
]phenyl}pyrimidin-2-amine
##STR00056##
[0587] Preparation of Intermediate 13.1
2-Chloro-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-5-fluoro-pyrimidine
##STR00057##
[0589] Intermediate 13.1 was prepared under similar conditions as
described in the preparation of Intermediate 9.1 using
2,4-dichloro-5-fluoropyrimidine (Aldrich Chemical Company Inc.) and
2,3-dihydro-1,4-benzodioxin-5-ylboronic acid (Combi-Blocks
Inc.).
[0590] .sup.1H-NMR (400 MHz, DMSO-d.sub.6, 300K): .delta.
[ppm]=8.94 (d, 1H), 7.12-7.07 (m, 1H), 7.07-6.97 (m, 2H), 4.33-4.25
(m, 4H).
Preparation of End Product
[0591] Example 13 was prepared under similar conditions as
described in the preparation of Example 9 using
2-chloro-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-5-fluoropyrimidine,
3-[(methylsulfonyl)methyl]aniline (Intermediate 1.3),
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and potassium
phosphate. The batch was purified by preparative HPLC.
[0592] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 300K) .delta. [ppm]=9.86
(s, 1H), 8.56 (d, 1H), 7.78-7.73 (m, 2H), 7.32-7.26 (m, 1H),
7.07-7.02 (m, 2H), 7.02-6.96 (m, 2H), 4.41 (s, 2H), 4.32-4.25 (m,
4H), 2.89 (s, 3H).
EXAMPLE 14
N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyph-
enyl)pyrimidin-2-amine
##STR00058##
[0593] Preparation of End Product
[0594] Example 14 was prepared under similar conditions as
described in the preparation of Example 9 using
2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine
(Intermediate 1.4), 3-[(cyclopropylsulfonyl)methyl]aniline
(Intermediate 10.2),
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and potassium
phosphate. The batch was purified by preparative HPLC.
[0595] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 300K) .delta. [ppm]=9.85
(s, 1H), 8.55 (d, 1H), 7.80 (d, 1H), 7.72 (dd, 1H), 7.55 (dd, 1H),
7.28 (t, 1H), 7.12 (dd, 1H), 7.00 (d, 1H), 6.95 (td, 1H), 4.42 (s,
2H), 3.84 (s, 3H), 2.56-2.52 (m, 1H), 1.02-0.76 (m, 4H).
EXAMPLE 15
N-{3-[(Benzylsulfonyl)methyl]phenyl}-5-fluoro-4-(4-fluoro-2-methoxyphenyl)-
-pyrimidin-2-amine
##STR00059##
[0596] Preparation of Intermediate 15.1
1-[(Benzylsulfanyl)methyl]-3-nitrobenzene
##STR00060##
[0598] Sulfur (2.23 g; 67.6 mmol) was added portionswise into a
stirred solution of benzylmagnesium bromide in THF (12%; 100.0 ml;
61.4 mmol). The resulting solution was stirred at 50.degree. C. for
1 hour and then cooled to 0.degree. C. Lithium
tetrahydridoaluminate (1.28 g; 33.78 mmol) was cautiously added
under stirring. The batch was stirred for 30 minutes at 50.degree.
C. and cooled to 0.degree. C. again. Water (4 ml) was cautiously
added under stirring. Finally, sulfuric acid (5%; 250 ml) was
cautiously added and the batch was stirred for 10 minutes. The
organic phase was separated and the aqueous phase was extracted
with diethyl ether (2.times.). The combined organic phases were
washed with saturated aqueous ammonium chloride solution
(2.times.), aqueous sodium bicarbonate solution (5%, 2.times.),
water (2.times.) and saturated aqueous sodium chloride solution
(2.times.). The organic phase was dried (Na.sub.2SO.sub.4) and
filtered before it was slowly added to a stirred batch of
1-(chloromethyl)-3-nitrobenzene (5.27 g; 30.7 mmol) and potassium
carbonate (6.36 g; 46.1 mmol) in DMF (100 ml). The batch was
stirred at 85.degree. C. over night. After cooling, the batch was
filtered over celite and concentrated in vacuo.
[0599] The residue was dissolved in ethyl acetate and washed with
water (2.times.) and saturated aqueous sodium chloride solution
(2.times.). The organic phase was dried (Na.sub.2SO.sub.4),
filtered and concentrated. The residue was purified by
chromatography (hexane/ethyl acetate 8:2) to give the desired
product (5.65 g; 20.7 mmol).
[0600] .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) .delta.=8.14-8.06
(m, 2H), 7.76-7.71 (m, 1H), 7.63-7.58 (m, 1H), 7.34-7.19 (m, 5H),
3.83 (s, 2H), 3.69 (s, 2H).
Preparation of Intermediate 15.2
1-[(Benzylsulfonyl)methyl]-3-nitrobenzene
##STR00061##
[0602] Intermediate 16.2 was prepared under similar conditions as
described in the preparation of Example 1.2 using
1-[(benzylsulfanyl)methyl]-3-nitrobenzene. The batch was purified
by chromatography (dichloromethane/ethanol).
[0603] .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) .delta.=8.25-8.18
(m, 2H), 7.80 (d, 1H), 7.70-7.64 (m, 1H), 7.35 (s, 5H), 4.68 (s,
2H), 4.50 (s, 2H).
Preparation of Intermediate 15.3
3-[(Benzylsulfonyl)methyl]aniline
##STR00062##
[0605] Intermediate 16.3 was prepared under similar conditions as
described in the preparation of Example 1.3 using
1-[(benzylsulfonyl)methyl]-3-nitrobenzene.
[0606] .sup.1H NMR (400 MHz, d.sub.6-DMSO, 300K) .delta.=7.39 (d,
5H), 7.01 (t, 1H), 6.59-6.53 (m, 2H), 6.50 (d, 1H), 5.16 (s, 2H),
4.42 (s, 2H), 4.25 (s, 2H).
Preparation of End Product
[0607] Example 15 was prepared under similar conditions as
described in the preparation of Example 9 using
2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine
(Intermediate 1.4), 3-[(benzylsulfonyl)-methyl]aniline
(Intermediate 15.3),
chloro(2-dicyclohexylphosphino-2',4',6'-tri-iso-propyl-1,1'-biphenyl)[2-(-
2-aminoethyl)phenyl] palladium(II) methyl-tert-butylether adduct,
2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl and potassium
phosphate. The batch was purified by preparative HPLC.
[0608] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 300K) .delta. [ppm]=9.87
(s, 1H), 8.55 (d, 1H), 7.81-7.71 (m, 2H), 7.53 (dd, 1H), 7.39 (s,
5H), 7.29 (t, 1H), 7.08 (dd, 1H), 6.96 (d, 1H), 6.90 (td, 1H), 4.47
(s, 2H), 4.39 (s, 2H), 3.82 (s, 3H).
EXAMPLE 16
5-Fluoro-4-[4-fluoro-2-(pyridin-3-ylmethoxy)phenyl]-N-{3-[(methylsulfonyl)-
methyl]phenyl}pyrimidin-2-amine
##STR00063##
[0609] Preparation of Intermediate 16.1
2-Chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine
##STR00064##
[0611] Intermediate 16.1 was prepared under similar conditions as
described in the preparation of Intermediate 1.4 using
2,4-dichloro-5-fluoropyrimidine (Aldrich Chemical Company Inc.) and
(2,4-difluorophenyl)boronic acid (ABCR GmbH & CO. KG).
[0612] .sup.1H-NMR (300 MHz, CDCl.sub.3, 300K): .delta. [ppm]=8.58
(s, 1H), 7.82-7.67 (m, 1H), 7.17-7.04 (m, 1H), 7.04-6.93 (m,
1H).
Preparation of Intermediate 16.2
4-(2,4-Difluorophenyl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]-phenyl}pyrim-
idin-2-amine
##STR00065##
[0614] Example 16.2 was prepared under similar conditions as
described in the preparation of Example 3. using
2-chloro-4-(2,4-difluorophenyl)-5-fluoropyrimidine (Intermediate
16.1) and 3-[(methylsulfonyl)methyl]aniline (Intermediate 1.3). The
batch was purified by preparative HPLC.
[0615] .sup.1H NMR (400 MHz, DMSO-d.sub.6, 300K) .delta. [ppm]=9.95
(s, 1H), 8.67 (d, 1H), 7.90-7.77 (m, 2H), 7.71 (dd, 1H), 7.47 (ddd,
1H), 7.36-7.27 (m, 2H), 7.01 (d, 1H), 4.42 (s, 2H), 2.90 (s,
3H).
Preparation of End Product
[0616] 3-(Hydroxymethyl)pyridine (139 mg, 1.27 mmol, ABCR GmbH
& CO. KG) was dissolved in DMF (2 ml), sodium hydride (55%
suspension in mineral oil, 55 mg, 127 mmol) was added and the
mixture was stirred for 30 minutes.
4-(2,4-Difluorophenyl)-5-fluoro-N-{3-[(methylsulfonyl)-methyl]ph-
enyl}-pyrimidin-2-amine (100 mg; 0.25 mmol) was added and the batch
was stirred at room temperature for 6 hours. The reaction mixture
was added to brine and the batch was extracted with ethyl acetate
(2.times.). The combined organic phases were washed with brine,
dried (sodium sulfate), and concentrated. The residue was purified
by preparative HPLC to give the desired product (44.3 mg; 91
.mu.mol).
[0617] .sup.1H-NMR (400 MHz, CDCl.sub.3, 300K): .delta. [ppm]=8.64
(d, 1H), 8.58 (dd, 1H), 8.30 (d, 1H), 7.82 (s, 1H), 7.69 (d, 1H),
7.60-7.52 (m, 2H), 7.35 (t, 1H), 7.30 (dd, 1H), 7.23 (s, 1H), 7.06
(d, 1H), 6.88 (td, 1H), 6.82 (dd, 1H), 5.14 (s, 2H), 4.24 (s, 2H),
2.76 (s, 3H).
EXAMPLE 17
5-Fluoro-4-{2-fluoro-4-[(4-fluorobenzyl)oxy]phenyl}-N-{3-[(methylsulfonyl)-
methyl]phenyl}pyrimidin-2-amine
##STR00066##
[0619] Example 17 was prepared under similar conditions as
described in the preparation of Example 16 using
4-(2,4-difluorophenyl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phenyl}pyrim-
idin-2-amine (Intermediate 16.2) and (4-fluorophenyl)methanol (ABCR
GmbH & CO. KG). The batch was purified by preparative HPLC.
[0620] .sup.1H-NMR (400 MHz, CDCl.sub.3, 300K): .delta. [ppm]=8.30
(d, 1H), 7.82 (s, 1H), 7.62-7.49 (m, 2H), 7.39-7.30 (m, 3H), 7.21
(s, 1H), 7.10-7.00 (m, 3H), 6.85 (td, 1H), 6.79 (dd, 1H), 5.09 (s,
2H), 4.23 (s, 2H), 2.76 (s, 3H).
EXAMPLE 18
5-Fluoro-4-{2-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-N-{3-[(methylsulfonyl)-
methyl]phenyl}pyrimidin-2-amine
##STR00067##
[0622] Example 18 was prepared under similar conditions as
described in the preparation of Example 16 using
4-(2,4-difluorophenyl)-5-fluoro-N-{3-[(methylsulfonyl)methyl]phenyl}pyrim-
idin-2-amine (Intermediate 16.2) and (3-fluorophenyl)methanol (ABCR
GmbH & CO. KG). The batch was purified by preparative HPLC.
[0623] 1H-NMR (400 MHz, CDCl.sub.3, 300K): .delta. [ppm]=8.33 (d,
1H), 7.83 (m, 1H), 7.61-7.52 (m, 2H), 7.39-7.29 (m, 2H), 7.26-7.23
(m, 1H), 7.15-6.97 (m, 4H), 6.86 (td, 1H), 6.77 (dd, 1H), 5.12 (s,
2H), 4.24 (s, 2H), 2.76 (s, 3H).
[0624] The following Table 1 provides an overview on the compounds
described in the example section:
TABLE-US-00010 TABLE 1 Example No. Structure Name of compound 1
##STR00068## 5-Fluoro-4-(4-fluoro-2- methoxyphenyl)-N-{3-
[(methylsulfonyl)methyl]phenyl} pyrimidin-2-amine 2 ##STR00069##
4-[2-(Benzyloxy)-4-fluorophenyl]-5- fluoro-N-{3-
[(methylsulfonyl)methyl]phenyl} pyrimidin-2-amine 3 ##STR00070##
4-[2-(Benzyloxy)-4-fluorophenyl]-5- fluoro-N-(3-{[(2-
methoxyethyl)sulfonyl]methyl}phenyl) pyrimidin-2-amine 4
##STR00071## 4-[2-(Benzyloxy)-4-fluorophenyl]-N- {3-[(tert-
butylsulfonyl)methyl]phenyl}-5- fluoropyrimidin-2-amine 5
##STR00072## 4-[2-(Benzyloxy)-4-fluorophenyl]-5-
fluoro-N-{3-[(propan-2- ylsulfonyl)methyl]phenyl}pyrimidin- 2-amine
6 ##STR00073## 4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-
[(cyclohexylsulfonyl)methyl]phenyl}- 5-fluoropyrimidin-2-amine 7
##STR00074## 5-Fluoro-4-(4-fluoro-2-
methoxyphenyl)-N-{3-[(propan-2- ylsulfonyl)methyl]phenyl}pyrimidin-
2-amine 8 ##STR00075## 2-[(3-{[5-fluoro-4-(4-fluoro-2-
methoxyphenyl)pyrimidin-2- yl]amino}benzyl)sulfonyl]ethanol 9
##STR00076## 4-(3,4-Dihydro-2H-chromen-8-yl)-5- fluoro-N-{3-
[(methylsulfonyl)methyl]phenyl} pyrimidin-2-amine 10 ##STR00077##
N-{3- [(Cyclopropylsulfonyl)methyl]phenyl}-
4-(3,4-dihydro-2H-chromen-8-yl)-5- fluoropyrimidin-2-amine 11
##STR00078## 4-[2-(Benzyloxy)-4-fluorophenyl]-5-
fluoro-N-{3-fluoro-5- [(methylsulfonyl)methyl]phenyl}
pyrimidin-2-amine 12 ##STR00079## 5-Fluoro-4-(4-fluoro-2-
methoxyphenyl)-N-{3-fluoro-5- [(methylsulfonyl)methyl]phenyl}
pyrimidin-2-amine 13 ##STR00080##
4-(2,3-Dihydro-1,4-benzodioxin-5-yl)- 5-fluoro-N-{3-
[(methylsulfonyl)methyl]phenyl} pyrimidin-2-amine 14 ##STR00081##
N-{3- [(Cyclopropylsulfonyl)methyl]phenyl}- 5-fluoro-4-(4-fluoro-2-
methoxyphenyl)pyrimidin-2-amine 15 ##STR00082## N-{3-
[(Benzylsulfonyl)methyl]phenyl}-5- fluoro-4-(4-fluoro-2-
methoxyphenyl)pyrimidin-2-amine 16 ##STR00083##
5-Fluoro-4-[4-fluoro-2-(pyridin-3- ylmethoxy)phenyl]-N-{3-
[(methylsulfonyl)- methyl]phenyl}pyrimidin-2-amine 17 ##STR00084##
5-Fluoro-4-{2-fluoro-4-[(4- fluorobenzyl)oxy]phenyl}-N-{3-
[(methylsulfonyl)- methyl]phenyl}pyrimidin-2-amine 18 ##STR00085##
5-Fluoro-4-{2-fluoro-4-[(3- fluorobenzyl)oxy]phenyl}-N-{3-
[(methylsulfonyl)- methyl]phenyl}pyrimidin-2-amine
Results:
TABLE-US-00011 [0625] TABLE 2 Inhibition for CDK9 and CDK2 of
compounds according to the present invention Table 2 {circle around
(1)} Name of compound {circle around (2)} {circle around (3)}
{circle around (4)} 1 5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3- 4
nM 300 nM 7 nM [(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 2
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3- 8 nM 840 nM 8 nM
[(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 3
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-(3-{[(2- 10 nM 1200 nM
10 nM methoxyethyl)sulfonyl]methyl}phenyl)pyrimidin- 2-amine 4
4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3-[(tert- 29 nM 3100 nM 80 nM
butylsulfonyl)methyl]phenyl}-5-fluoropyrimidin- 2-amine 5
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3- 14 nM 1600 nM 20 nM
[(propan-2-ylsulfonyl)methyl]phenyl}pyrimidin-2- amine 6
4-[2-(Benzyloxy)-4-fluorophenyl]-N-{3- 51 nM 20000 nM 98 nM
[(cyclohexylsulfonyl)methyl]phenyl}-5- fluoropyrimidin-2-amine 7
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3- 13 nM 510 nM 120 nM
[(propan-2-ylsulfonyl)methyl]phenyl}pyrimidin-2- amine 8
2-[(3-{[5-fluoro-4-(4-fluoro-2- 9 nM 310 nM 103 nM
methoxyphenyl)pyrimidin-2- yl]amino}benzyl)sulfonyl]ethanol 9
4-(3,4-Dihydro-2H-chromen-8-yl)-5-fluoro-N-{3- 9 nM 300 nM 47 nM
[(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 10
N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-4- 10 nM 210 nM 80 nM
(3,4-dihydro-2H-chromen-8-yl)-5- fluoropyrimidin-2-amine 11
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-{3- 24 nM 1100 nM 40 nM
fluoro-5- [(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 12
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3- 6 nM 200 nM 16 nM
fluoro-5- [(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 13
4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-5-fluoro-N- 6 nM 120 nM 5 nM
{3-[(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 14
N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-5- 8 nM 780 nM 40 nM
fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin-2- amine 15
N-{3-[(Benzylsulfonyl)methyl]phenyl}-5-fluoro- 10 nM 1100 nM 83 nM
4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-amine 16
5-Fluoro-4-{2-fluoro-4-[(3- 8 nM 820 nM 19 nM
fluorobenzyl)oxy]phenyl}-N-{3-
[(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 17
5-Fluoro-4-{2-fluoro-4-[(3- 12 nM 3800 nM 6 nM
fluorobenzyl)oxy]phenyl}-N-{3-
[(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 18
5-Fluoro-4-{2-fluoro-4-[(3- 19 nM 880 nM 8 nM
fluorobenzyl)oxy]phenyl}-N-{3-
[(methylsulfonyl)-methyl]phenyl}pyrimidin-2- amine The IC.sub.50
(inhibitory concentration at 50% of maximal effect) values are
indicated in nM or .mu.M, "n.t." means that the compounds have not
been tested in this assay. {circle around (1)}: Example Number
{circle around (2)}: CDK9: CDK9/CycT1 kinase assay as described
under Method 1a. of Materials and Methods {circle around (3)}:
CDK2: CDK2/CycE kinase assay as described under Method 2. of
Materials and Methods {circle around (4)}: high ATP CDK9:
CDK9/CycT1 kinase assay as described under Method 1b. of Materials
and Methods
TABLE-US-00012 TABLE 3 Inhibition of proliferation of HeLa,
HeLa-MaTu-ADR, NCI-H460, DU145, Caco-2 and B16F10 cells by
compounds according to the present invention, determined as
described under Method 3. of Materials and Methods. Name of
compound 1 5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3- 0.29 0.17
0.33 0.29 0.26 0.31 n.t.
[(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine 2
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N- 0.35 0.30 0.37 0.41
0.49 0.82 n.t. {3-[(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine
3 4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N-(3- 1.2 1.0 1.2 1.3
1.1 1.2 n.t. {[(2-methoxyethyl)sulfonyl]methyl}phenyl)
pyrimidin-2-amine 7 5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N- {3-
1.1 n.t. n.t. n.t. n.t. n.t. n.t.
[(propan-2-ylsulfonyl)methy]phenyl}pyrimidin- 2-amine 8
2-[(3-{[5-fluoro-4-(4-fluoro-2- 1.0 0.38 0.71 0.64 0.71 0.95 n.t.
methoxyphenyl)pyrimidin-2- yl]amino}benzyl)sulfonyl]ethanol 9
4-(3,4-Dihydro-2H-chromen-8-yl)-5-fluoro-N- 0.36 0.20 0.34 0.32
0.27 0.34 n.t. {3-[(methylsulfonyl)methyl]phenyl}pyrimidin-2- amine
10 N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-4- 1.1 n.t. n.t. n.t.
n.t. n.t. n.t. (3,4-dihydro-2H-chromen-8-yl)-5-
fluoropyrimidin-2-amine 11
4-[2-(Benzyloxy)-4-fluorophenyl]-5-fluoro-N- 1.0 n.t. n.t. n.t.
n.t. n.t. n.t. {3-fluoro-5-[(methylsulfonyl)methyl]phenyl}
pyrimidin-2-amine 12 5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N-{3-
0.11 0.12. 0.36 0.31 0.38 0.36 0.11
fluoro-5-[(methylsulfonyl)methyl]phenyl} pyrimidin-2-amine 13
4-(2,3-Dihydro-1,4-benzodioxin-5-yl)-5-fluoro- 0.21 0.19 0.34 0.31
0.22 0.51 n.t. N-{3-[(methylsulfonyl)methyl]phenyl}
pyrimidin-2-amine 14 N-{3-[(Cyclopropylsulfonyl)methyl]phenyl}-5-
0.67 n.t. n.t. n.t. n.t n.t n.t.
fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidin- 2-amine 15
N-{3-[(Benzylsulfonyl)methyl]phenyl}-5-fluoro- 1.8 n.t. n.t. n.t.
n.t. n.t. n.t. 4-(4-fluoro-2-methoxyphenyl)pyrimidin-2-amine 16
5-Fluoro-4-[4-fluoro-2-(pyridin-3- 0.38 0.35 0.32 0.3 0.44 0.41
n.t. ylmethoxy)phenyl]-N-{3-[(methylsulfonyl)-
methyl]phenyl}pyrimidin-2-amine 17 5-Fluoro-4-{2-fluoro-4-[(4- 0.62
0.35 0.46 0.5 0.55 0.49 n.t. fluorobenzyl)oxy]phenyl}-N-{3-
[(methylsulfonyl)-methyl]phenyl} pyrimidin-2-amine 18
5-Fluoro-4-{2-fluoro-4-[(3- 0.12 0.04 0.1 0.14 0.1 0.11 n.t.
fluorobenzyl)oxy]phenyl}-N-{3- [(methylsulfonyl)-methyl]phenyl}
pyrimidin-2-amine All IC.sub.50 (inhibitory concentration at 50% of
maximal effect) values are indicated in .mu.M, "n.t." means that
the compounds have not been tested in this assay. : Example Number
: Inhibition of HeLa cell proliferation : Inhibition of
HeLa-MaTu-ADR cell proliferation : Inhibition of NCI-H460 cell
proliferation : Inhibition of DU145 cell proliferation : Inhibition
of Caco-2 cell proliferation : Inhibition of B16F10 cell
proliferation : Inhibition of A2780 cell proliferation
TABLE-US-00013 TABLE 4 Caco-2 permeation of compounds according to
the present invention, determined as described under Method 4. of
Materials and Methods. Table 4 {circle around (1)} Name of compound
{circle around (2)} {circle around (3)} {circle around (4)} {circle
around (5)} 1 5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N- 2 206 85
0.41 {3- [(methylsulfonyl)methyl]phenyl}pyrimidin- 2-amine 12
5-Fluoro-4-(4-fluoro-2-methoxyphenyl)-N- 2 97 31 0.32 {3-fluoro-5-
[(methylsulfonyl)methyl]phenyl}pyrimidin- 2-amine {circle around
(1)}: Example Number {circle around (2)}: Concentration of test
compound indicated in .mu.M. {circle around (3)}: P.sub.app A-B
(M.sub.ari) indicated in [nm/s] {circle around (4)}: P.sub.app B-A
(M.sub.ari) indicated in [nm/s] {circle around (5)}: Efflux
ratio
* * * * *